BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous stud...BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC.The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells.We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells.Finally,we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.RESULTS Compared to normal mucosa,REG4 mRNA expression was high in CRC(P<0.05)but protein expression was low.An inverse correlation existed between lymph node and distant metastases,tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression(P<0.05),but vice versa for REG4 protein expression.REG4-related genes included:Chemokine activity;taste receptors;protein-DNA and DNA packing complexes;nucleosomes and chromatin;generation of second messenger molecules;programmed cell death signals;epigenetic regulation and DNA methylation;transcription repression and activation by DNA binding;insulin signaling pathway;sugar metabolism and transfer;and neurotransmitter receptors(P<0.05).REG4 exposure or overexpression promoted proliferation,antiapoptosis,migration,and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway.REG4 was involved in chemoresistance not through de novo lipogenesis,but lipid droplet assembly.REG4 inhibited the transcription of acetyl-CoA carboxylase 1(ACC1)and ATP-citrate lyase(ACLY)by disassociating the complex formation of anti-acetyl(AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly.REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.展开更多
BACKGROUND Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a newly discovered oncogene.It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer(GC)cells.CIP2A is func...BACKGROUND Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a newly discovered oncogene.It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer(GC)cells.CIP2A is functionally related to chemoresistance in various types of tumors according to recent studies.The underlying mechanism,however,is unknown.Further,the primary treatment regimen for GC is oxaliplatin-based chemotherapy.Nonetheless,it often fails due to chemoresistance of GC cells to oxaliplatin.AIM The goal of this study was to examine CIP2A expression and its association with oxaliplatin resistance in human GC cells.METHODS Immunohistochemistry was used to examine CIP2A expression in GC tissues and adjacent normal tissues.CIP2A expression in GC cell lines was reduced using small interfering RNA.After confirming the silencing efficiency,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium and flow cytometry assays were used to evaluate cell proliferation and apoptosis caused by oxaliplatin treatment.Further,the key genes and protein changes were verified using realtime quantitative reverse transcription PCR and Western blotting,respectively,before and after intervention.For bioinformatics analysis,we used the R software and Bioconductor project.For statistical analysis,we used GraphPad Prism 6.0 and the Statistical Package for the Social Sciences software version 20.0(IBM,Armonk,United States).RESULTS A high level of CIP2A expression was associated with tumor size,T stage,lymph node metastasis,Tumor Node Metastasis stage,and a poor prognosis.Further,CIP2A expression was higher in GC cells than in normal human gastric epithelial cells.Using small interfering RNA against CIP2A,we discovered that CIP2A knockdown inhibited cell proliferation and significantly increased GC cell sensitivity to oxaliplatin.Moreover,CIP2A knockdown enhanced oxaliplatin-induced apoptosis in GC cells.Hence,high CIP2A levels in GC may be a factor in chemoresistance to oxaliplatin.In human GC cells,CIP2A regulated protein kinase B phosphorylation,and chemical inhibition of the protein kinase B signaling pathway was significantly associated with increased sensitivity to oxaliplatin.Therefore,the protein kinase B signaling pathway was correlated with CIP2Aenhanced chemoresistance of human GC cells to oxaliplatin.CONCLUSION CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.展开更多
The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ...The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.展开更多
Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study lever...Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study leverages computational tools to dissect the differential gene expression profiles in retinoblastoma. Methods: Employing an in silico approach, we analyzed gene expression data from public repositories by applying rigorous statistical models, including limma and de seq 2, for identifying differentially expressed genes DEGs. Our findings were validated through cross-referencing with independent datasets and existing literature. We further employed functional annotation and pathway analysis to elucidate the biological significance of these DEGs. Results: Our computational analysis confirmed the dysregulation of key retinoblastoma-associated genes. In comparison to normal retinal tissue, RB1 exhibited a 2.5-fold increase in expression (adjusted p Conclusions: Our analysis reinforces the critical genetic alterations known in retinoblastoma and unveils new avenues for research into the disease’s molecular basis. The discovery of chemoresistance markers and immune-related genes opens potential pathways for personalized treatment strategies. The study’s outcomes emphasize the power of in silico analyses in unraveling complex cancer genomics.展开更多
Background:The chemoresistance of prostate cancer(PCa)is invariably associated with the aggressiveness and metastasis of this disease.New emerging evidence indicates that the epithelial-to-mesenchymal transition(EMT)m...Background:The chemoresistance of prostate cancer(PCa)is invariably associated with the aggressiveness and metastasis of this disease.New emerging evidence indicates that the epithelial-to-mesenchymal transition(EMT)may play pivotal roles in the development of chemoresistance and metastasis.As a hallmark of EMT,E-cadherin is suggested to be a key marker in the development of chemoresistance.However,the molecular mechanisms underlying PCa chemoresistance remain unclear.The current study aimed to explore the association between EMT and chemoresistance in PCa as well as whether changing the expression of E-cadherin would affect PCa chemoresistance.Methods:Parental PC3 and DU145 cells and their chemoresistant PC3-Tx R and DU145-Tx R cells were analyzed.PC3-Tx R and DU145-Tx R cells were transfected with E-cadherin-expressing lentivirus to overexpress E-cadherin;PC3 and DU145 cells were transfected with small interfering RNA to silence E-cadherin.Changes of EMT phenotype-related markers and signaling pathways were assessed by Western blotting and quantitative real-time polymerase chain reaction.Tumor cell migration,invasion,and colony formation were then evaluated by wound healing,transwell,and colony formation assays,respectively.The drug sensitivity was evaluated using MTS assay.Results:Chemoresistant PC3-Tx R and DU145-Tx R cells exhibited an invasive and metastatic phenotype that associated with EMT,including the down-regulation of E-cadherin and up-regulation of Vimentin,Snail,and N-cadherin,comparing with that of parental PC3 and DU145 cells.When E-cadherin was overexpressed in PC3-Tx R and DU145-Tx R cells,the expression of Vimentin and Claudin-1 was down-regulated,and tumor cell migration and invasion were inhibited.In particular,the sensitivity to paclitaxel was reactivated in E-cadherin-overexpressing PC3-Tx R and DU145-Tx R cells.When E-cadherin expression was silenced in parental PC3 and DU145 cells,the expression of Vimentin and Snail was up-regulated,and,particularly,the sensitivity to paclitaxel was decreased.Interestingly,Notch-1 expression was up-regulated in PC3-Tx R and DU145-Tx R cells,whereas the E-cadherin expression was down-regulated in these cells comparing with their parental cells.The use ofγ-secretase inhibitor,a Notch signaling pathway inhibitor,significantly increased the sensitivity of chemoresistant cells to paclitaxel.Conclusion:The down-regulation of E-cadherin enhances PCa chemoresistance via Notch signaling,and inhibiting the Notch signaling pathway may reverse PCa chemoresistance.展开更多
Gastric cancer(GC) is the fourth most common cancer worldwide and ranks second in global cancer mortality statistics. Perioperative chemotherapy plays an important role in the management and treatment of advanced stag...Gastric cancer(GC) is the fourth most common cancer worldwide and ranks second in global cancer mortality statistics. Perioperative chemotherapy plays an important role in the management and treatment of advanced stage disease. However,response to chemotherapy varies widely,with some patients presenting no or only minor response to treatment. Hence,chemotherapy resistance is a major clinical problem that impacts on outcome. Unfortunately,to date there are no reliable biomarkers available that predict response to chemotherapy before the start of the treatment,or that allow modification of chemotherapy resistance. MicroRNAs(miRNAs) could provide an answer to this problem. miRNAs are involved in the initiation and progression of a variety of cancer types,and there is evidence that miRNAs impact on resistance towards chemotherapeutic drugs as well. This current review aims to provide an overview about the potential clinical applicability of miRNAs as biomarkers for chemoresistance in GC.The authors focus in this context on the potential of miRNAs to predict sensitivity towards different chemotherapeutics,and on the potential of miRNAs to modulate sensitivity and resistance towards chemotherapy in GC.展开更多
Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States.The majority of patients are candidates only for palliative chemotherapy,which has proven largely ineffective in halting ...Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States.The majority of patients are candidates only for palliative chemotherapy,which has proven largely ineffective in halting tumor progression.One proposed mechanism of chemoresistance involves signaling via the mesenchymalepithelial transition factor protein(MET),a previously established pathway critical to cell proliferation and migration.Here,we review the literature to characterize the role of MET in the development of tumorigenesis,metastasis and chemoresistance,highlighting the potential of MET as a therapeutic target in pancreatic cancer.In this review,we characterize the role of c-Met in the development of tumorigenesis,metastasis and chemoresistance,highlighting the potential of c-Met as a therapeutic target in pancreatic cancer.展开更多
Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and re...Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.展开更多
Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervica...Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.展开更多
BACKGROUND Obesity is a recognized risk factor for endometrial cancer (EmCa) and other cancer types. Leptin levels are significantly increased in obese individuals. Leptin-induced signaling crosstalk [Notch, Interleuk...BACKGROUND Obesity is a recognized risk factor for endometrial cancer (EmCa) and other cancer types. Leptin levels are significantly increased in obese individuals. Leptin-induced signaling crosstalk [Notch, Interleukin-1 (IL-1) and leptin outcome, NILCO] has been associated with breast cancer progression. This complex signaling crosstalk affects cancer cell proliferation, migration, invasion, angiogenesis, apoptosis and chemoresistance. NILCO expression was previously detected in human EmCa. However, it is unknown whether leptin regulates NILCO and alters EmCa’s response to chemotherapeutics. It is hypothesized that leptin induces NILCO and increases aggressiveness and chemoresistance in EmCa cells. AIM To determine whether leptin induces NILCO molecules in EmCa affecting cell proliferation, aggressiveness and chemoresistance. METHODS Leptin’s effects on the expression of NILCO molecules [mRNAs and proteins for Notch receptors (Notch1-4), ligands (JAG1 and DLL4) and downstream effectors (survivin, Hey2), and leptin (OB-R) and IL-1 (IL-1R tI) receptors] was examined in EmCa cells (type I: Ishikawa, and HEC-1A, and type II: An3Ca and KLE) using Real-time PCR and Western blot analysis, respectively. In addition, the effects of leptin on cell cycle, proliferation and cell invasion were determined using cytometric analysis (Cellometer Vision CBA system), MTT cell proliferation and Matrigel-based invasion assays, respectively. Inhibitors of leptin (nanoparticlebound leptin peptide receptor antagonist-2, IONP-LPrA2), IL-1 (anti-IL-1R tI antibody) and Notch (siRNA interference RNA) were used to investigate NILCO’s effects on cell proliferation and invasion. Leptin’s effects on Paclitaxel cytotoxicity in EmCa cells was determined by the CCK8 and Cellometer-based Annexin V assays. RESULTS For the first time it was shown that leptin is an inducer of Notch in EmCa. Experimental data suggest that leptin induced the expression of NILCO molecules, promoted proliferation and S- phase progression, and reduced Paclitaxel cytotoxicity on EmCa cells. Leptin’s effects were higher in type II EmCa cells. The progression of this more aggressive form of the disease is associated with obesity. Remarkably, the use of the leptin signaling antagonist, IONPLPrA2, re-sensitized EmCa cells to Paclitaxel. CONCLUSION Present data suggest the notion that leptin-induced NILCO could be a link between obesity and EmCa progression and chemoresistance. Most aggressive type II EmCa cells were higher sensitive to leptin, which appears to increase proliferation, cell cycle progression, aggressiveness, and chemoresistance to Paclitaxel. Therefore, leptin and NILCO could be novel therapeutic targets for type II EmCa, which does not have targeted therapy. Overall, IONP-LPrA2 has a potential as a novel adjuvant drug to enhance the effectiveness of type II EmCa chemotherapy.展开更多
AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were...AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RTPCR and Western blot were used to detect the mR NA and protein expression of drug resistance gene 1(MDR1), respectively.RESULTS: GD protected CRC cells from drug-induced apoptosis(oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug resensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.展开更多
Hepatocellular carcinoma(HCC) has an elevated mortality rate, largely because of high recurrence and metastasis. Additionally, the main obstacle during treatment of HCC is that patients usually develop resistance to c...Hepatocellular carcinoma(HCC) has an elevated mortality rate, largely because of high recurrence and metastasis. Additionally, the main obstacle during treatment of HCC is that patients usually develop resistance to chemotherapy.Cancer drug resistance involves many different mechanisms, including alterations in drug metabolism and processing, impairment of the apoptotic machine, activation of cell survival signaling, decreased drug sensitivity and autophagy, among others. Nowadays, miRNAs are emerging as master regulators of normal physiology-and tumor-related gene expression. In HCC,aberrant expression of many miRNAs leads to chemoresistance. Herein, we particularly analyzed miRNA impact on HCC resistance to drug therapy. Certain miRNAs target ABC(ATP-binding cassette) transporter genes. As most of these miRNAs are downregulated in HCC, transporter levels increase and intracellular drug accumulation decrease, turning cells less sensitive to death. Others miRNAs target autophagy-related gene expression, inhibiting autophagy and acting as tumor suppressors. Nevertheless, due to its downregulation in HCC, these miRNAs do not inhibit autophagy or tumor growth and, resistance is favored.Concluding, modulation of ABC transporter and/or autophagy-related gene expression or function by miRNAs could be determinant for HCC cell survival under chemotherapeutic drug treatment. Undoubtedly, more insights on the biological processes, signaling pathways and/or molecular mechanisms regulated by miRNAs are needed. Anyway, miRNA-based therapy together with conventional chemotherapeutic drugs has a great future in cancer therapy.展开更多
BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different C...BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.展开更多
Chemotherapeutics are validated conventional treatments for patients with advanced cancer.However,with continual application of chemotherapeutics,chemoresistance,which is often predictive of poor prognosis,has gradual...Chemotherapeutics are validated conventional treatments for patients with advanced cancer.However,with continual application of chemotherapeutics,chemoresistance,which is often predictive of poor prognosis,has gradually become a concern in recent years.Circular RNAs(circ RNAs),a class of endogenous noncoding RNAs(nc RNAs)with a closed-loop structure,have been reported to be notable targets and markers for the prognosis,diagnosis,and treatment of many diseases,particularly cancer.Although dozens of studies have shown that circ RNAs play major roles in drug-resistance activity in tumors,the mechanisms by which circ RNAs affect chemoresistance have yet to be explored.In this review,we describe the detailed mechanisms of circ RNAs and chemotherapeutics in various cancers and summarize potential therapeutic targets for drug-resistant tumors.展开更多
Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,c...Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,cellsignalling and inflammation.Indeed,an increased LD content is one of the mostapparent features resulting from lipid metabolism reprogramming necessary tosupport the basic functions of cancer cells.LDs have been associated to differentcellular processes involved in cancer progression and aggressiveness,such astumorigenicity,invasion and metastasis,as well as chemoresistance.Interestingly,all of these processes are controlled by a subpopulation of highly aggressivetumoral cells named cancer stem cells(CSCs),suggesting that LDs may befundamental elements for stemness in cancer.Considering the key role of CSCs onchemoresistance and disease relapse,main factors of therapy failure,the design ofnovel therapeutic approaches targeting these cells may be the only chance forlong-term survival in cancer patients.In this sense,their biology and functionalproperties render LDs excellent candidates for target discovery and design ofcombined therapeutic strategies.In this review,we summarise the currentknowledge identifying LDs and CSCs as main contributors to cancer aggressiveness,metastasis and chemoresistance.展开更多
X-ray repair cross-complementing protein 1(XRCC1)could repair cisplatin-induced DNA damage.XRCC1 Arg399Gln and Arg194Trp variants alter XRCC1 expression and function,leading to changes in cancer sensitivity to cisplat...X-ray repair cross-complementing protein 1(XRCC1)could repair cisplatin-induced DNA damage.XRCC1 Arg399Gln and Arg194Trp variants alter XRCC1 expression and function,leading to changes in cancer sensitivity to cisplatin treatment.This study aimed to investigate the effects of XRCC1 Arg399Gln and Arg194Trp polymorphisms on cell viability,apoptosis and XRCC1 expression in cisplatin-sensitive A549 and cisplatin-resistant A549/DDP non-small cell lung cancer(NSCLC)cells.Plasmids carrying XRCC1 Arg399Gln and Arg194Trp were constructed and transfected into A549 and A549/DDP cells.RT-PCR,Western blot,MTT assay,and flow cytometry analysis were performed to assess cell viability,apoptosis,and XRCC1 expression.Compared to control cells,the viability of A549 and A549/DDP cells transfected with XRCC1 Arg399Gln and Arg194Trp was higher and the apoptosis rate was lower,and XRCC1 mRNA and protein expression levels were significantly higher.In conclusion,our results suggest that XRCC1 Arg399Gln and Arg194Trp polymorphisms change XRCC1 expression in NSCLC cells and alter the sensitivity of NSCLC to cisplatin-based chemotherapy.展开更多
Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogene...Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogeneous with diverse subpopulations of distinct genotypes and phenotypes and the frequency of CTCs is correlated with poor prognosis and overall survival in cancer patients.Less than 0.01%of them may eventually generate metastatic tumors in secondary sites,indicating the inefficiency of metastasis.Nevertheless,metastasis accounts for over 90%of cancer-related deaths,suggesting that a subpopulation of CTCs are able to survive the metastatic process and form metastases.To target metastasis,it is thus essential to understand the roles of various factors during dissemination in the survival and functions of CTCs.However,the effects of hemodynamic shear stress on biophysical properties and functions of CTCs in suspension are not fully understood.This study was to investigate the effect of hemodynamic shear stress on the survival and anti-chemotherapy ability of suspended circulating tumor cells during metastasis,and the effect of actomyosin activity on this regulation.In this study,we developed a circulatory system to generate physiologic levels of hemodynamic shear stress,which mimicked certain important aspects of the CTC microenvironment in blood circulation.The survival of tumor cells in suspension,as a model for real CTCs,under different shear stress and circulation duration was examined.We found that the majority of breast tumor cells s in suspension can be eliminated by hemodynamic shear stress.The surviving cells exhibit unique biophysical properties,including significantly retarded cell adhesion,mesenchymal-like cell morphology,and reduced F-actin expression and cellular stiffness.Cancer stem cells which has been reported in other papers have lower stiffness compared with conventional tumor cells showed significantly higher survival in blood flow.Importantly,low actomyosin activity promotes the survival of CTCs in blood shear flow while high actomyosin activity inhibits tumor cells surviving shear stress treatment.These findings might be explained by the up-and down-regulation of the anti-apoptosis genes.Soft surviving tumor cells held survival advantages in shear flow and higher resistance to chemotherapy.Metastasis is closely linked with chemoresistance.However,the underlying mechanisms have not been fully understood,in particular,the roles of hemodynamic shear stress and actomyosin-dependent cell mechanics in drug resistance of CTCs remain unclear.Inhibiting actomyosin activity in suspended tumor cells enhanced chemoresistance,while activating actomyosin suppressed this ability.These findings might be associated with the corresponding changes in multidrug resistance related genes.Our study unveils the regulatory roles of actomyosin in the survival and drug resistance of circulating tumor cells in hemodynamic shear flow,which imply the importance of fluid shear stress and actomyosin activity in tumor metastasis.Our findings reveal a new mechanism by which circulating tumor cells are able to survive hemodynamic shear stress and chemotherapy and may offer a new potential strategy to target circulating tumor cells in shear flow and combat chemoresistance through actomyosin.展开更多
Objective:Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition,not only aiding seeding and colonization,but also rendering the tumor cells generally chemoresistant.We pre...Objective:Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition,not only aiding seeding and colonization,but also rendering the tumor cells generally chemoresistant.We previously found that upregulated E-cadherin in the epithelial micrometastases activated canonical survival pathways,including PI3K-Akt,that protected the tumor cells from death;however,the extent of protection from blocking the pathway in its entirety was modest,because different isoforms may have alternately affected cell functioning.Here,we characterized Akt isoform expressions in primary and metastatic prostate cancers,as well as their individual contributions to chemoresistance.Methods:Akt isoforms and E-cadherin were manipulated with drugs,knocked down,and over expressed.Tumor cell killing was determined in vitro and in vivo.Overall survival was calculated from patient records and specimens.Results:Pan-Akt inhibition sensitized tumor cells to chemotherapy,and specific blockade of Akt1 or/and Akt2 caused cells to be more chemoresponsive.Overexpression of Akt3 induced apoptosis.A low dose of Akt1 or Akt2 inhibitor enabled standard chemotherapies to significantly eradicate metastatic prostate tumors in a mouse model,acting as chemosensitizers.In human specimens,we found Akt1 and Akt2 positively correlated,whereas Akt3 inversely correlated,with the overall survival of prostate cancer patients.Akt1high/Akt2high/Akt3low tumors had the worst outcomes.Conclusions:E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance,whereas Akt3 made cells more fragile.These findings emphasized the need to target Akt1/2,rather than pan-Akt,as a rational therapeutic approach.展开更多
OBJECTIVE Doxorubicin-based therapy has been found to be not significantly effective for the treatment of advanced stage hepatocellular carcinomas(HCCs),which often undergo epithelial-mesenchymal transition(EMT)during...OBJECTIVE Doxorubicin-based therapy has been found to be not significantly effective for the treatment of advanced stage hepatocellular carcinomas(HCCs),which often undergo epithelial-mesenchymal transition(EMT)during tumor progression.Increasing evidence suggest(s)that epithelial cell transformation to mesenchymal state canenhance the ability to self-renew and confer greater resistance to the conventional chemotherapeutic drugs.The aim of this study was to examine the potential efficacyof ascochlorin,an isoprenoid antibiotic to overcome drug resistance induced by doxorubicin in HCC cell lines and to elucidate its underlying mechanism(s)of action.METHODS The effect of doxorubicin and ascochlorin on HCC cell lines was determined by MTT,Western blotting,immunofluorescence and NF-кB DNA binding assays.RESULTS Our results indicate that HCC cells that show a mesenchymal-like phenotype,are resistance to the doxorubicin therapy which directly correlated with an increased slug expression.We also observed that activation of NF-кB pathway plays an essential role in doxorubicin induced-chemoresistance and pharmacological inhibition of this pathway with ascochlorin can significantly reverse drug-induced invasion/migration and resistance in HCC cells.CONCLUSION Our results indicate that combination treatment of doxorubicin with ascochlorin has the potential to inhibit HCC growth and metastasis.展开更多
BACKGROUND Gastric cancer(GC)is a common malignancy that results in a high rate of cancerrelated mortality.Cisplatin(DDP)-based chemotherapy is the first-line clinical treatment for GC therapy,but chemotherapy resista...BACKGROUND Gastric cancer(GC)is a common malignancy that results in a high rate of cancerrelated mortality.Cisplatin(DDP)-based chemotherapy is the first-line clinical treatment for GC therapy,but chemotherapy resistance remains a severe clinical challenge.Zinc oxide nanoparticle(ZnO-NP)has been identified as a promising anti-cancer agent,but the function of ZnO-NP in GC development is still unclear.AIM To explore the effect of ZnO-NP on chemotherapy resistance during GC progression.METHODS ZnO-NP was synthesized,and the effect and underlying mechanisms of ZnO-NP on the malignant progression and chemotherapy resistance of GC cells were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assays,colony formation assays,transwell assays,wound healing assays,flow cytometry,and Western blot analysis in GC cells and DDP-resistant GC cells,and by tumorigenicity analyses in nude mice.RESULTS Our data revealed that ZnO-NP was able to inhibit proliferation,migration,and invasion and induce apoptosis of GC cells.Meanwhile,ZnO-NP significantly reduced the half maximal inhibitory concentration(IC50)of DDP for the inhibition of cell proliferation of DDP-resistant SGC7901/DDP cell lines.Autophagy was increased in DDP-resistant GC cells,as demonstrated by elevated light chain 3-like protein 2(LC3II)/LC3I and Beclin-1 expression and repressed p62 expression in SGC7901/DDP cells compared to SGC7901 cells.Mechanically,ZnO-NP inhibited autophagy in GC cells and treatment with DDP induced autophagy,which was reversed by ZnO-NP.Functionally,ZnO-NP attenuated the tumor growth of DDP-resistant GC cells in vivo.CONCLUSION We conclude that ZnO-NP alleviates the chemoresistance of GC cells by inhibiting autophagy.Our findings present novel insights into the mechanism by which ZnO-NP regulates the chemotherapy resistance of GC.ZnO-NP may serve as a potential therapeutic candidate for GC treatment.The potential role of ZnO-NP in the clinical treatment of GC needs clarification in future investigations.展开更多
基金Natural Science Foundation of Hebei Province,No.21377772DNo.H2022406034National Natural Scientific Foundation of China,No.81672700.
文摘BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC.The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells.We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells.Finally,we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.RESULTS Compared to normal mucosa,REG4 mRNA expression was high in CRC(P<0.05)but protein expression was low.An inverse correlation existed between lymph node and distant metastases,tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression(P<0.05),but vice versa for REG4 protein expression.REG4-related genes included:Chemokine activity;taste receptors;protein-DNA and DNA packing complexes;nucleosomes and chromatin;generation of second messenger molecules;programmed cell death signals;epigenetic regulation and DNA methylation;transcription repression and activation by DNA binding;insulin signaling pathway;sugar metabolism and transfer;and neurotransmitter receptors(P<0.05).REG4 exposure or overexpression promoted proliferation,antiapoptosis,migration,and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway.REG4 was involved in chemoresistance not through de novo lipogenesis,but lipid droplet assembly.REG4 inhibited the transcription of acetyl-CoA carboxylase 1(ACC1)and ATP-citrate lyase(ACLY)by disassociating the complex formation of anti-acetyl(AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly.REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
基金Supported by This work was supported by the Natural Science Foundation of Gansu Province,China,No.17JR5RA272 and No.22JR5RA923the Research Fund Project of The First Hospital of Lanzhou University,No.ldyyyn2021-120,No.ldyyyn2020-98 and No.ldyyyn2021-30.
文摘BACKGROUND Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a newly discovered oncogene.It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer(GC)cells.CIP2A is functionally related to chemoresistance in various types of tumors according to recent studies.The underlying mechanism,however,is unknown.Further,the primary treatment regimen for GC is oxaliplatin-based chemotherapy.Nonetheless,it often fails due to chemoresistance of GC cells to oxaliplatin.AIM The goal of this study was to examine CIP2A expression and its association with oxaliplatin resistance in human GC cells.METHODS Immunohistochemistry was used to examine CIP2A expression in GC tissues and adjacent normal tissues.CIP2A expression in GC cell lines was reduced using small interfering RNA.After confirming the silencing efficiency,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium and flow cytometry assays were used to evaluate cell proliferation and apoptosis caused by oxaliplatin treatment.Further,the key genes and protein changes were verified using realtime quantitative reverse transcription PCR and Western blotting,respectively,before and after intervention.For bioinformatics analysis,we used the R software and Bioconductor project.For statistical analysis,we used GraphPad Prism 6.0 and the Statistical Package for the Social Sciences software version 20.0(IBM,Armonk,United States).RESULTS A high level of CIP2A expression was associated with tumor size,T stage,lymph node metastasis,Tumor Node Metastasis stage,and a poor prognosis.Further,CIP2A expression was higher in GC cells than in normal human gastric epithelial cells.Using small interfering RNA against CIP2A,we discovered that CIP2A knockdown inhibited cell proliferation and significantly increased GC cell sensitivity to oxaliplatin.Moreover,CIP2A knockdown enhanced oxaliplatin-induced apoptosis in GC cells.Hence,high CIP2A levels in GC may be a factor in chemoresistance to oxaliplatin.In human GC cells,CIP2A regulated protein kinase B phosphorylation,and chemical inhibition of the protein kinase B signaling pathway was significantly associated with increased sensitivity to oxaliplatin.Therefore,the protein kinase B signaling pathway was correlated with CIP2Aenhanced chemoresistance of human GC cells to oxaliplatin.CONCLUSION CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.
基金supported by Academic Leader Training Program of Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13).
文摘The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.
文摘Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study leverages computational tools to dissect the differential gene expression profiles in retinoblastoma. Methods: Employing an in silico approach, we analyzed gene expression data from public repositories by applying rigorous statistical models, including limma and de seq 2, for identifying differentially expressed genes DEGs. Our findings were validated through cross-referencing with independent datasets and existing literature. We further employed functional annotation and pathway analysis to elucidate the biological significance of these DEGs. Results: Our computational analysis confirmed the dysregulation of key retinoblastoma-associated genes. In comparison to normal retinal tissue, RB1 exhibited a 2.5-fold increase in expression (adjusted p Conclusions: Our analysis reinforces the critical genetic alterations known in retinoblastoma and unveils new avenues for research into the disease’s molecular basis. The discovery of chemoresistance markers and immune-related genes opens potential pathways for personalized treatment strategies. The study’s outcomes emphasize the power of in silico analyses in unraveling complex cancer genomics.
基金supported by National Natural Science Foundation of China(NSFC)Key Project(No.81130046)NSFC(Nos.81272415 and 81171993)+1 种基金Guangxi Key Projects(No.2013GXNSFEA053004)Youth Science Foundation of Guangxi Medical University(No.GXMUYSF201539)
文摘Background:The chemoresistance of prostate cancer(PCa)is invariably associated with the aggressiveness and metastasis of this disease.New emerging evidence indicates that the epithelial-to-mesenchymal transition(EMT)may play pivotal roles in the development of chemoresistance and metastasis.As a hallmark of EMT,E-cadherin is suggested to be a key marker in the development of chemoresistance.However,the molecular mechanisms underlying PCa chemoresistance remain unclear.The current study aimed to explore the association between EMT and chemoresistance in PCa as well as whether changing the expression of E-cadherin would affect PCa chemoresistance.Methods:Parental PC3 and DU145 cells and their chemoresistant PC3-Tx R and DU145-Tx R cells were analyzed.PC3-Tx R and DU145-Tx R cells were transfected with E-cadherin-expressing lentivirus to overexpress E-cadherin;PC3 and DU145 cells were transfected with small interfering RNA to silence E-cadherin.Changes of EMT phenotype-related markers and signaling pathways were assessed by Western blotting and quantitative real-time polymerase chain reaction.Tumor cell migration,invasion,and colony formation were then evaluated by wound healing,transwell,and colony formation assays,respectively.The drug sensitivity was evaluated using MTS assay.Results:Chemoresistant PC3-Tx R and DU145-Tx R cells exhibited an invasive and metastatic phenotype that associated with EMT,including the down-regulation of E-cadherin and up-regulation of Vimentin,Snail,and N-cadherin,comparing with that of parental PC3 and DU145 cells.When E-cadherin was overexpressed in PC3-Tx R and DU145-Tx R cells,the expression of Vimentin and Claudin-1 was down-regulated,and tumor cell migration and invasion were inhibited.In particular,the sensitivity to paclitaxel was reactivated in E-cadherin-overexpressing PC3-Tx R and DU145-Tx R cells.When E-cadherin expression was silenced in parental PC3 and DU145 cells,the expression of Vimentin and Snail was up-regulated,and,particularly,the sensitivity to paclitaxel was decreased.Interestingly,Notch-1 expression was up-regulated in PC3-Tx R and DU145-Tx R cells,whereas the E-cadherin expression was down-regulated in these cells comparing with their parental cells.The use ofγ-secretase inhibitor,a Notch signaling pathway inhibitor,significantly increased the sensitivity of chemoresistant cells to paclitaxel.Conclusion:The down-regulation of E-cadherin enhances PCa chemoresistance via Notch signaling,and inhibiting the Notch signaling pathway may reverse PCa chemoresistance.
文摘Gastric cancer(GC) is the fourth most common cancer worldwide and ranks second in global cancer mortality statistics. Perioperative chemotherapy plays an important role in the management and treatment of advanced stage disease. However,response to chemotherapy varies widely,with some patients presenting no or only minor response to treatment. Hence,chemotherapy resistance is a major clinical problem that impacts on outcome. Unfortunately,to date there are no reliable biomarkers available that predict response to chemotherapy before the start of the treatment,or that allow modification of chemotherapy resistance. MicroRNAs(miRNAs) could provide an answer to this problem. miRNAs are involved in the initiation and progression of a variety of cancer types,and there is evidence that miRNAs impact on resistance towards chemotherapeutic drugs as well. This current review aims to provide an overview about the potential clinical applicability of miRNAs as biomarkers for chemoresistance in GC.The authors focus in this context on the potential of miRNAs to predict sensitivity towards different chemotherapeutics,and on the potential of miRNAs to modulate sensitivity and resistance towards chemotherapy in GC.
文摘Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States.The majority of patients are candidates only for palliative chemotherapy,which has proven largely ineffective in halting tumor progression.One proposed mechanism of chemoresistance involves signaling via the mesenchymalepithelial transition factor protein(MET),a previously established pathway critical to cell proliferation and migration.Here,we review the literature to characterize the role of MET in the development of tumorigenesis,metastasis and chemoresistance,highlighting the potential of MET as a therapeutic target in pancreatic cancer.In this review,we characterize the role of c-Met in the development of tumorigenesis,metastasis and chemoresistance,highlighting the potential of c-Met as a therapeutic target in pancreatic cancer.
基金Supported by Department of Defense(DOD)Congressionally Direct Medical Research Program(CDMRP)+3 种基金No.W81XWH-13-1-0382National Institute of Health(NIH)/National Cancer Institute(NCI),No.1R41CA183399-01APilot Project Award from MSM(Morehouse School of Medicine)/Tuskegee University/University of Alabama in Birmingham(UAB)Cancer Center partnership,No.5U54CA118638the National Institute on Minority Health and Health Disparities(NIMHD)of NIH,No.5S21MD00101
文摘Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.
基金the Joint Funds for the Innovation of Science and Technology Program of Fujian Province,China(2018Y9110)the Natural Science Foundation of Fujian Province,China,(2020J011126)the China Postdoctoral Science Foundation(2021T140468).
文摘Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.
基金Supported by the National Cancer Institute at the National Institutes of Health,No.S21 MD000101,No.5G12 MD0076021,No.G12RR026250-03,No.NIH RR030341C06,No.RR18386 to Morehouse School of Medicinethe National Institute of General Medical Sciences,National Institutes of Health,No.5T32HL103104-04 to DDB
文摘BACKGROUND Obesity is a recognized risk factor for endometrial cancer (EmCa) and other cancer types. Leptin levels are significantly increased in obese individuals. Leptin-induced signaling crosstalk [Notch, Interleukin-1 (IL-1) and leptin outcome, NILCO] has been associated with breast cancer progression. This complex signaling crosstalk affects cancer cell proliferation, migration, invasion, angiogenesis, apoptosis and chemoresistance. NILCO expression was previously detected in human EmCa. However, it is unknown whether leptin regulates NILCO and alters EmCa’s response to chemotherapeutics. It is hypothesized that leptin induces NILCO and increases aggressiveness and chemoresistance in EmCa cells. AIM To determine whether leptin induces NILCO molecules in EmCa affecting cell proliferation, aggressiveness and chemoresistance. METHODS Leptin’s effects on the expression of NILCO molecules [mRNAs and proteins for Notch receptors (Notch1-4), ligands (JAG1 and DLL4) and downstream effectors (survivin, Hey2), and leptin (OB-R) and IL-1 (IL-1R tI) receptors] was examined in EmCa cells (type I: Ishikawa, and HEC-1A, and type II: An3Ca and KLE) using Real-time PCR and Western blot analysis, respectively. In addition, the effects of leptin on cell cycle, proliferation and cell invasion were determined using cytometric analysis (Cellometer Vision CBA system), MTT cell proliferation and Matrigel-based invasion assays, respectively. Inhibitors of leptin (nanoparticlebound leptin peptide receptor antagonist-2, IONP-LPrA2), IL-1 (anti-IL-1R tI antibody) and Notch (siRNA interference RNA) were used to investigate NILCO’s effects on cell proliferation and invasion. Leptin’s effects on Paclitaxel cytotoxicity in EmCa cells was determined by the CCK8 and Cellometer-based Annexin V assays. RESULTS For the first time it was shown that leptin is an inducer of Notch in EmCa. Experimental data suggest that leptin induced the expression of NILCO molecules, promoted proliferation and S- phase progression, and reduced Paclitaxel cytotoxicity on EmCa cells. Leptin’s effects were higher in type II EmCa cells. The progression of this more aggressive form of the disease is associated with obesity. Remarkably, the use of the leptin signaling antagonist, IONPLPrA2, re-sensitized EmCa cells to Paclitaxel. CONCLUSION Present data suggest the notion that leptin-induced NILCO could be a link between obesity and EmCa progression and chemoresistance. Most aggressive type II EmCa cells were higher sensitive to leptin, which appears to increase proliferation, cell cycle progression, aggressiveness, and chemoresistance to Paclitaxel. Therefore, leptin and NILCO could be novel therapeutic targets for type II EmCa, which does not have targeted therapy. Overall, IONP-LPrA2 has a potential as a novel adjuvant drug to enhance the effectiveness of type II EmCa chemotherapy.
基金Supported by National Natural Science Foundation of China,No.81000867,No.81272299,No.81301784 and No.81301920Natural Science Foundation of Jiangsu Province,No.BK20150004 and No.BK20151108+3 种基金the Fundamental Research Funds for the Central Universities,No.NOJUSRP51619BMedical Key Professionals Program of Jiangsu Province,No.RC2011031"333" Talents Project of Jiangsu ProvinceHospital Management Center of Wuxi,No.YGZXM1524
文摘AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RTPCR and Western blot were used to detect the mR NA and protein expression of drug resistance gene 1(MDR1), respectively.RESULTS: GD protected CRC cells from drug-induced apoptosis(oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug resensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.
基金Agencia Nacional de Promoción Científica y Tecnológica-Fondo para la Investigación Científica y Tecnológica,No.PICT-2014-3216(to Espelt MV)CONICET,No.PIP-647+1 种基金UBA,No.Programación Científica 2016-2019,No.20020150100005BAANPCyT-FONCYT,No.PICT-2016-1139(all to Troncoso MF)
文摘Hepatocellular carcinoma(HCC) has an elevated mortality rate, largely because of high recurrence and metastasis. Additionally, the main obstacle during treatment of HCC is that patients usually develop resistance to chemotherapy.Cancer drug resistance involves many different mechanisms, including alterations in drug metabolism and processing, impairment of the apoptotic machine, activation of cell survival signaling, decreased drug sensitivity and autophagy, among others. Nowadays, miRNAs are emerging as master regulators of normal physiology-and tumor-related gene expression. In HCC,aberrant expression of many miRNAs leads to chemoresistance. Herein, we particularly analyzed miRNA impact on HCC resistance to drug therapy. Certain miRNAs target ABC(ATP-binding cassette) transporter genes. As most of these miRNAs are downregulated in HCC, transporter levels increase and intracellular drug accumulation decrease, turning cells less sensitive to death. Others miRNAs target autophagy-related gene expression, inhibiting autophagy and acting as tumor suppressors. Nevertheless, due to its downregulation in HCC, these miRNAs do not inhibit autophagy or tumor growth and, resistance is favored.Concluding, modulation of ABC transporter and/or autophagy-related gene expression or function by miRNAs could be determinant for HCC cell survival under chemotherapeutic drug treatment. Undoubtedly, more insights on the biological processes, signaling pathways and/or molecular mechanisms regulated by miRNAs are needed. Anyway, miRNA-based therapy together with conventional chemotherapeutic drugs has a great future in cancer therapy.
文摘BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.
基金supported in part by the National Natural Science Foundation of China(Grant Nos.81702435 and 82073133)the Natural Science Foundation of Jiangsu Province(Grant Nos.BK20170264 and BK20191154)the Six Talent Peaks Project in Jiangsu Province(Grant No.WSW-050)。
文摘Chemotherapeutics are validated conventional treatments for patients with advanced cancer.However,with continual application of chemotherapeutics,chemoresistance,which is often predictive of poor prognosis,has gradually become a concern in recent years.Circular RNAs(circ RNAs),a class of endogenous noncoding RNAs(nc RNAs)with a closed-loop structure,have been reported to be notable targets and markers for the prognosis,diagnosis,and treatment of many diseases,particularly cancer.Although dozens of studies have shown that circ RNAs play major roles in drug-resistance activity in tumors,the mechanisms by which circ RNAs affect chemoresistance have yet to be explored.In this review,we describe the detailed mechanisms of circ RNAs and chemotherapeutics in various cancers and summarize potential therapeutic targets for drug-resistant tumors.
基金Miguel Servet Fellowship,No.CP16/00121FIS(Fondo Investigaciones Sanitarias)grants,No.PI17/00082 and No.PI20/00942,all from Instituto de Salud Carlos Ⅲ and Cofinanced by European Funds(FSE:“El FSE invierte en tu futuro”and FEDER:“Una manera de hacer Europa,”respectively)and the Worldwide Cancer Research Charity together with Fundación Científica Asociación Española contra el Cáncer(FCAECC),No.19-0250.
文摘Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,cellsignalling and inflammation.Indeed,an increased LD content is one of the mostapparent features resulting from lipid metabolism reprogramming necessary tosupport the basic functions of cancer cells.LDs have been associated to differentcellular processes involved in cancer progression and aggressiveness,such astumorigenicity,invasion and metastasis,as well as chemoresistance.Interestingly,all of these processes are controlled by a subpopulation of highly aggressivetumoral cells named cancer stem cells(CSCs),suggesting that LDs may befundamental elements for stemness in cancer.Considering the key role of CSCs onchemoresistance and disease relapse,main factors of therapy failure,the design ofnovel therapeutic approaches targeting these cells may be the only chance forlong-term survival in cancer patients.In this sense,their biology and functionalproperties render LDs excellent candidates for target discovery and design ofcombined therapeutic strategies.In this review,we summarise the currentknowledge identifying LDs and CSCs as main contributors to cancer aggressiveness,metastasis and chemoresistance.
基金supported in part by grants from the Chongqing Municipal Science and Technology Commission(#2013jcyjA10125).
文摘X-ray repair cross-complementing protein 1(XRCC1)could repair cisplatin-induced DNA damage.XRCC1 Arg399Gln and Arg194Trp variants alter XRCC1 expression and function,leading to changes in cancer sensitivity to cisplatin treatment.This study aimed to investigate the effects of XRCC1 Arg399Gln and Arg194Trp polymorphisms on cell viability,apoptosis and XRCC1 expression in cisplatin-sensitive A549 and cisplatin-resistant A549/DDP non-small cell lung cancer(NSCLC)cells.Plasmids carrying XRCC1 Arg399Gln and Arg194Trp were constructed and transfected into A549 and A549/DDP cells.RT-PCR,Western blot,MTT assay,and flow cytometry analysis were performed to assess cell viability,apoptosis,and XRCC1 expression.Compared to control cells,the viability of A549 and A549/DDP cells transfected with XRCC1 Arg399Gln and Arg194Trp was higher and the apoptosis rate was lower,and XRCC1 mRNA and protein expression levels were significantly higher.In conclusion,our results suggest that XRCC1 Arg399Gln and Arg194Trp polymorphisms change XRCC1 expression in NSCLC cells and alter the sensitivity of NSCLC to cisplatin-based chemotherapy.
基金the support from National Natural Science Foundation of China ( 11672255)Shenzhen Science and Technology Innovation Commission ( JCYJ20170303160515987, JCYJ20170413154735522 )+1 种基金Early Career Scheme from Research Grants Council of the Hong Kong Special Administrative Region,China ( PolyU 252094 /17E)the internal grant from the Hong Kong Polytechnic University ( 1-ZE4Q,1-ZVJ8)
文摘Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogeneous with diverse subpopulations of distinct genotypes and phenotypes and the frequency of CTCs is correlated with poor prognosis and overall survival in cancer patients.Less than 0.01%of them may eventually generate metastatic tumors in secondary sites,indicating the inefficiency of metastasis.Nevertheless,metastasis accounts for over 90%of cancer-related deaths,suggesting that a subpopulation of CTCs are able to survive the metastatic process and form metastases.To target metastasis,it is thus essential to understand the roles of various factors during dissemination in the survival and functions of CTCs.However,the effects of hemodynamic shear stress on biophysical properties and functions of CTCs in suspension are not fully understood.This study was to investigate the effect of hemodynamic shear stress on the survival and anti-chemotherapy ability of suspended circulating tumor cells during metastasis,and the effect of actomyosin activity on this regulation.In this study,we developed a circulatory system to generate physiologic levels of hemodynamic shear stress,which mimicked certain important aspects of the CTC microenvironment in blood circulation.The survival of tumor cells in suspension,as a model for real CTCs,under different shear stress and circulation duration was examined.We found that the majority of breast tumor cells s in suspension can be eliminated by hemodynamic shear stress.The surviving cells exhibit unique biophysical properties,including significantly retarded cell adhesion,mesenchymal-like cell morphology,and reduced F-actin expression and cellular stiffness.Cancer stem cells which has been reported in other papers have lower stiffness compared with conventional tumor cells showed significantly higher survival in blood flow.Importantly,low actomyosin activity promotes the survival of CTCs in blood shear flow while high actomyosin activity inhibits tumor cells surviving shear stress treatment.These findings might be explained by the up-and down-regulation of the anti-apoptosis genes.Soft surviving tumor cells held survival advantages in shear flow and higher resistance to chemotherapy.Metastasis is closely linked with chemoresistance.However,the underlying mechanisms have not been fully understood,in particular,the roles of hemodynamic shear stress and actomyosin-dependent cell mechanics in drug resistance of CTCs remain unclear.Inhibiting actomyosin activity in suspended tumor cells enhanced chemoresistance,while activating actomyosin suppressed this ability.These findings might be associated with the corresponding changes in multidrug resistance related genes.Our study unveils the regulatory roles of actomyosin in the survival and drug resistance of circulating tumor cells in hemodynamic shear flow,which imply the importance of fluid shear stress and actomyosin activity in tumor metastasis.Our findings reveal a new mechanism by which circulating tumor cells are able to survive hemodynamic shear stress and chemotherapy and may offer a new potential strategy to target circulating tumor cells in shear flow and combat chemoresistance through actomyosin.
基金These studies were enabled by a VA Merit Award and a grant from the National Institutes of Health(USA)(Grant Nos.NCATS and NCI,UH3TR000496)the US Department of Defense(Grant No.DOD BCRP W81XWH1910495)funding from the National Natural Science Foundation of China(Grant No.82073212).
文摘Objective:Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition,not only aiding seeding and colonization,but also rendering the tumor cells generally chemoresistant.We previously found that upregulated E-cadherin in the epithelial micrometastases activated canonical survival pathways,including PI3K-Akt,that protected the tumor cells from death;however,the extent of protection from blocking the pathway in its entirety was modest,because different isoforms may have alternately affected cell functioning.Here,we characterized Akt isoform expressions in primary and metastatic prostate cancers,as well as their individual contributions to chemoresistance.Methods:Akt isoforms and E-cadherin were manipulated with drugs,knocked down,and over expressed.Tumor cell killing was determined in vitro and in vivo.Overall survival was calculated from patient records and specimens.Results:Pan-Akt inhibition sensitized tumor cells to chemotherapy,and specific blockade of Akt1 or/and Akt2 caused cells to be more chemoresponsive.Overexpression of Akt3 induced apoptosis.A low dose of Akt1 or Akt2 inhibitor enabled standard chemotherapies to significantly eradicate metastatic prostate tumors in a mouse model,acting as chemosensitizers.In human specimens,we found Akt1 and Akt2 positively correlated,whereas Akt3 inversely correlated,with the overall survival of prostate cancer patients.Akt1high/Akt2high/Akt3low tumors had the worst outcomes.Conclusions:E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance,whereas Akt3 made cells more fragile.These findings emphasized the need to target Akt1/2,rather than pan-Akt,as a rational therapeutic approach.
基金The project supported in part by agrant from National Medical Research Council of Singapore
文摘OBJECTIVE Doxorubicin-based therapy has been found to be not significantly effective for the treatment of advanced stage hepatocellular carcinomas(HCCs),which often undergo epithelial-mesenchymal transition(EMT)during tumor progression.Increasing evidence suggest(s)that epithelial cell transformation to mesenchymal state canenhance the ability to self-renew and confer greater resistance to the conventional chemotherapeutic drugs.The aim of this study was to examine the potential efficacyof ascochlorin,an isoprenoid antibiotic to overcome drug resistance induced by doxorubicin in HCC cell lines and to elucidate its underlying mechanism(s)of action.METHODS The effect of doxorubicin and ascochlorin on HCC cell lines was determined by MTT,Western blotting,immunofluorescence and NF-кB DNA binding assays.RESULTS Our results indicate that HCC cells that show a mesenchymal-like phenotype,are resistance to the doxorubicin therapy which directly correlated with an increased slug expression.We also observed that activation of NF-кB pathway plays an essential role in doxorubicin induced-chemoresistance and pharmacological inhibition of this pathway with ascochlorin can significantly reverse drug-induced invasion/migration and resistance in HCC cells.CONCLUSION Our results indicate that combination treatment of doxorubicin with ascochlorin has the potential to inhibit HCC growth and metastasis.
文摘BACKGROUND Gastric cancer(GC)is a common malignancy that results in a high rate of cancerrelated mortality.Cisplatin(DDP)-based chemotherapy is the first-line clinical treatment for GC therapy,but chemotherapy resistance remains a severe clinical challenge.Zinc oxide nanoparticle(ZnO-NP)has been identified as a promising anti-cancer agent,but the function of ZnO-NP in GC development is still unclear.AIM To explore the effect of ZnO-NP on chemotherapy resistance during GC progression.METHODS ZnO-NP was synthesized,and the effect and underlying mechanisms of ZnO-NP on the malignant progression and chemotherapy resistance of GC cells were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assays,colony formation assays,transwell assays,wound healing assays,flow cytometry,and Western blot analysis in GC cells and DDP-resistant GC cells,and by tumorigenicity analyses in nude mice.RESULTS Our data revealed that ZnO-NP was able to inhibit proliferation,migration,and invasion and induce apoptosis of GC cells.Meanwhile,ZnO-NP significantly reduced the half maximal inhibitory concentration(IC50)of DDP for the inhibition of cell proliferation of DDP-resistant SGC7901/DDP cell lines.Autophagy was increased in DDP-resistant GC cells,as demonstrated by elevated light chain 3-like protein 2(LC3II)/LC3I and Beclin-1 expression and repressed p62 expression in SGC7901/DDP cells compared to SGC7901 cells.Mechanically,ZnO-NP inhibited autophagy in GC cells and treatment with DDP induced autophagy,which was reversed by ZnO-NP.Functionally,ZnO-NP attenuated the tumor growth of DDP-resistant GC cells in vivo.CONCLUSION We conclude that ZnO-NP alleviates the chemoresistance of GC cells by inhibiting autophagy.Our findings present novel insights into the mechanism by which ZnO-NP regulates the chemotherapy resistance of GC.ZnO-NP may serve as a potential therapeutic candidate for GC treatment.The potential role of ZnO-NP in the clinical treatment of GC needs clarification in future investigations.
