AIM:To investigate the association between nuclearβ-catenin overexpression in rectal adenocarcinoma and radioresistance.METHODS:A retrospective analysis was conducted.The analysis involved 136 patients with locally a...AIM:To investigate the association between nuclearβ-catenin overexpression in rectal adenocarcinoma and radioresistance.METHODS:A retrospective analysis was conducted.The analysis involved 136 patients with locally advanced rectal adenocarcinoma who underwent shortcourse preoperative radiotherapy and radical resection.The expression ofβ-catenin in both pretreatment biopsy specimens and resected primary tumor tissues was examined by immunohistochemistry.The correlation ofβ-catenin expression with radioresistance was evaluated using the tumor regression grading(TRG)system.The relationship betweenβ-catenin expression and clinicopathological characteristics was also analyzed.Univariate and logistic multivariate regression analyses were adopted to determine the independent factors of radioresistance.RESULTS:Nuclearβ-catenin overexpression was more evident in radioresistant rectal adenocarcinoma than in radiosensitive rectal adenocarcinoma(57.6%vs 16.7%,P<0.001).Nuclearβ-catenin was overexpressed in favor of poor TRG(≤2),whereas membraneβ-catenin was expressed in favor of good TRG(≥3).Nuclearβ-catenin expression in tumor cell differentiation(P=0.018),lymph node metastasis(P=0.022),and TRG(P<0.001)showed significant differences.Univariate analyses demonstrated that radioresistance is associated with nuclearβ-catenin overexpression(P<0.001).In addition,logistic multivariate regression analysis indicated that only three factors,namely,tumor size(P<0.001),tumor cell differentiation(P<0.001),and nuclearβ-catenin overexpression(P<0.001),are associated with radioresistance.By using radioresistance as a prediction target,nuclearβ-catenin-based prediction alone achieved 83%accuracy,65%sensitivity,and88%specificity.CONCLUSION:Nuclearβ-catenin overexpression may be a valuable candidate to predict the response of rectal adenocarcinoma to preoperative radiotherapy.展开更多
Hepatocellular carcinoma(HCC), one of the most common cancers in the world, is characterized by poor prognosis and recurrence after resection. Its prevalence is highest in developing countries, particularly where ther...Hepatocellular carcinoma(HCC), one of the most common cancers in the world, is characterized by poor prognosis and recurrence after resection. Its prevalence is highest in developing countries, particularly where there is high incidence of hepatitis B virus infection. Several curative treatments are available for early stage HCC; however, these options are not available for advanced disease. New techniques allowing the specific delivery of high-dose radiotherapy enable their use in the treatment of HCC, which has been avoided in the past due to low hepatic tolerance for radiation. This presents a new challenge—the development of resistance to radiotherapy and subsequent disease recurrence. Recently, the mechanisms controlling radioresistance have begun to be elucidated. Understanding the molecular basis of radioresistance is key to developing new strategies with better treatment response and increased patient survival.展开更多
We present evidence here that abundantly expressed b-catenin-triggered NF-kB-dependent upregulation of inducible nitric oxide synthase(iNOS) found in hepatoma Mahlavu cells (RT-resistant variant designated as RR-Mal),...We present evidence here that abundantly expressed b-catenin-triggered NF-kB-dependent upregulation of inducible nitric oxide synthase(iNOS) found in hepatoma Mahlavu cells (RT-resistant variant designated as RR-Mal), but not in Hep 3B cells (RT-sensitive variant designated as RS-3B) is a key element contribrting to the radioresisitance through the activation of two prominent radioprotective pathways. First, high iNOS expression found in RR-Mal, but not in RS-3B cells was found to perturb calcium homeostasis that triggered ER stress response leading to the overproduction of ER chaperone GRP-78 via robust generation of cleaved ATF-6a (50 kDa) subunits and their nuclear translocation. Meanwhile, both abundantly expressed NF-κB and COX-2 found in RR-Mal cells could also provoke an increased production of PGE2 resulting in robust production of Bcl-2. Interestingly, when RR-Mal cells were treated with PDTC (a NF-κB inhibitor) or celecoxib (a COX-2 inhibitor), a concentration-dependent downregulation of Bcl-2 could be demonstrated implying that Bcl-2 overexpression was indeed mediated through NF-κB/Cox-2/PGE2 pathway. Importantly, we also unveiled that siRNA-mediated silencing of survivin in RR-Mal cells could result in a concomitant downregulation of GRP-78 due to a severe inhibition of ATF-6a (50 kDa) expression. Taken together, our data demonstrate that constitutively overexpressed b-catenin/NF-κB/iNOS and NF-κB/COX-2/PGE2 pathways that overproducing GRP-78, survivin and Bcl-2 expressions are responsible for radioresistance acquisition in RR-Mal cells. Thus, both pathways could be served as potential targets for overcoming radioresistance.展开更多
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer, which is the leading cause of death in lung cancer patient. Routine treatment of NSCLC cannot effectively change the survival rate of patients, one i...Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer, which is the leading cause of death in lung cancer patient. Routine treatment of NSCLC cannot effectively change the survival rate of patients, one important reason is the increased radioresistance of tumor cells after conventional radiotherapy.展开更多
The molecular mechanisms of radioresistance of manganese ssuperoxide dismutase (MnSOD) was investigated in thisstudy. We assayed cell necrocis and apoptosis induced by ionizing radiation. Furthermore, the possible rol...The molecular mechanisms of radioresistance of manganese ssuperoxide dismutase (MnSOD) was investigated in thisstudy. We assayed cell necrocis and apoptosis induced by ionizing radiation. Furthermore, the possible roles of oncogenes bc1-2and p53 mRNA expression in MnSOD gene-transfected cells were for investigated. me results showed that 10 Gy X-ray could induce the expression of bc1-2 mRNA and suppress p53 mRNA expression in sense MnSOD transfected cells, whereas Bc1-2 mRNAexpression did not change and p53 mRNA expression increased in antisense MnSOD transfected cells. It is suggested that Bc1-2 isrequired for the radioresistance of MnSOD and the status of p53 play a role in radiation-induced cell death.展开更多
Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divid...Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.展开更多
Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical applica...Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical application.The innate immune sensing receptor retinoic acid-inducible gene I(RIG-I)is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma.To date,the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated.Here,we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo.Transcriptome analysis pointed to a central role for p53,which was confirmed using p53^(-/-)B16 cells.In vivo,the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53^(-/-)B16 tumours,while the antitumoural response to RIG-I stimulation alone was maintained.Our results identify p53 as a pivotal checkpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death.Thus,the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway,such as melanoma.展开更多
Small cell lung cancer(SCLC)is a highly aggressive tumor type for which limited therapeutic progress has been made.Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment,bu...Small cell lung cancer(SCLC)is a highly aggressive tumor type for which limited therapeutic progress has been made.Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment,but most patients with SCLC acquire therapeutic resistance.Given the need for more effective therapies,better elucidation of the molecular pathogenesis of SCLC is imperative.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors.This pathway is an important regulator of cancer cell glucose metabolism,and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC.Glucose metabolism has three main branches-aerobic glycolysis,oxidative phosphorylation,and the pentose phosphate pathway-involved in radioresistance.The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1(HIF-1)signaling.The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance,including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway.This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway,hypoxia,and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.展开更多
Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application,which is mainly caused by the aggravation of immunosuppressive tumor microenvironment(ITM).Especially tum...Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application,which is mainly caused by the aggravation of immunosuppressive tumor microenvironment(ITM).Especially tumor-associated macrophages(TAMs)usually display the tumor-promoting M2 phenotype during high-dose fractional radiotherapy mediating radiotherapy resistance.Herein,the toll like receptor agonist TLR7/8a was conjugated with radiosensitive peptide hydrogel(Smac-TLR7/8 hydrogel)to regulate TAMs repolarization from M2 type into M1 type,thus modulating the ITM and overcoming the radioresistance.The Smac-TLR7/8 hydrogel was fabricated through self-assembly with nanofibrous morphology,porous structure and excellent biocompatibility.Uponγ-ray radiation,Smac-TLR7/8 hydrogel effectively polarized the macrophages into M1 type.Notably,combined with radiotherapy,TAMs repolarization regulated by Smac-TLR7/8 hydrogel could increase tumor necrosis factor secretion,activate antitumor immune response and effectively inhibit tumor growth.Moreover,TAMs repolarization rebuilt the ITM and elicited the immunogenic phenotypes in solid tumors,thus enhanced the PD1-blockade efficacy through increasing tumor infiltrating lymphocytes(TILs)and decreasing Treg cells in two different immune activity tumor mice models.Overall,this study substantiated that recruiting and repolarization of TAMs were critical in eliciting antitumor immune response and overcoming radioresistance,thus improving the efficacy of radiotherapy and immunotherapy.展开更多
Hypoxia is a big roadblock for cancer radiotherapy,in which the hypoxia-inducible factor(HIF-1)creates a microenvironment and cancer cells’intrinsic signaling networks conferring radioresistance to cancers.HIF-1 is a...Hypoxia is a big roadblock for cancer radiotherapy,in which the hypoxia-inducible factor(HIF-1)creates a microenvironment and cancer cells’intrinsic signaling networks conferring radioresistance to cancers.HIF-1 is a heterodimeric transcription factor HIF-1α/HIF-1β,that regulates the transcription of a broad range of downstream genes possessing an E-box-like hypoxia response element(HRE).The expression of HIF-1αis oxygensensitive while HIF-1βis constitutively expressed.In addition to hypoxia,ionizing radiation can also induce the expression of HIF-1α.The HIF-1 modulates a set of signaling pathways to cause profound effects on the response of cancer to radiotherapy,including radiation-induced DNA damage response(DDR),vasculogenesis and glucose metabolism reprograming,epithelial mesenchymal transition(EMT),etc.In this review,our aim is to summarize the current knowledge about the role and the related signal pathways of HIF-1 in association with the resistance of cancers to radiotherapy.Targeting HIF-1 and its signal pathways is a promising strategy for sensitization of cancers to radiotherapy.展开更多
The conclusion based on transmission electron microscopy, "the tightly packed ring-like nucleoid of the Deinococcus radiodurans R1 is a key to radioresistance", has instigated lots of debates. In this study,...The conclusion based on transmission electron microscopy, "the tightly packed ring-like nucleoid of the Deinococcus radiodurans R1 is a key to radioresistance", has instigated lots of debates. In this study, according to the previous research of PprI’s crucial role in radioresistance of D. radiodurans, we have attempted to examine and compare the nucleoid morphology differences among wild-type D. ra-diodurans R1 strain, pprI function-deficient mutant (YR1), and pprI function-complementary strains (YR1001, YR1002, and YR1004) before and after exposure to ionizing irradiation. Fluorescence mi-croscopy images indicate: (1) the majority of nucleoid structures in radioresistant strain R1 cells ex-hibit the tightly packed ring-like morphology, while the pprI function-deficient mutant YR1 cells carrying predominate ring-like structure represent high sensitivity to irradiation; (2) as an extreme radioresistant strain similar to wild-type R1, pprI completely function-complementary strain YR1001 almost displays the loose and irregular nucleoid morphologies. On the other hand, another radioresistant pprI partly function-complementary strain YR1002’s nucleiods exhibit about 60% ring-like structure; (3) a PprI C-terminal deletion strain YR1004 consisting of approximately 60% of ring-like nucleoid is very sensi-tive to radiation. Therefore, our present experiments do not support the conclusion that the ring-like nucleoid of D. radiodurans does play a key role in radioresistance.展开更多
Objective:Hepatitis B X-interacting protein(HBXIP)plays an important role in breast tumorigenesis,tumor growth and metastasis,but its functional contribution in radioresistance remains poorly understood.As radiotherap...Objective:Hepatitis B X-interacting protein(HBXIP)plays an important role in breast tumorigenesis,tumor growth and metastasis,but its functional contribution in radioresistance remains poorly understood.As radiotherapy served as an essential adjuvant treatment,uncovering the role of HBXIP as well as its downstream molecular XIAP in radioresistance could benefit for the development of individual therapy strategy.Methods:Immunohistochemistry of 42 breast cancer tissue samples and Western blot analysis of proteins from MCF-7 and MDA-MB-231 cells exposed to fractioned doses(γ-rays)were used to identify the expression of HBXIP/XIAP in breast cancer.To verify the radioresistance effects and potential mechanism,the cells were treated with designed pCMV and siRNA of targeting genes,and then measured with MTT assay,clonogenic survival assay and flow cytometry.Furthermore,a subcutaneous xenotransplanted tumor model of breast cancer was established in nude mice to validate the radioresistization effect of HBXIP in vivo.Results:HBXIP and XIAP expression levels in breast cancer tissues were positively correlated with chemoradiotherapy resistance of breast cancer.Overexpression of HBXIP could desensitize MCF-7 and MDA-MB-231 cells to irradiation by inhibiting radiation-induced cell apoptosis,and knockdown of HBXIP in these cells had the converse response.Moreover,up-regulation of HBXIP resulted in the increase of XIAP and NF-κB levels in vitro and in vivo,while down-regulation of HBXIP led to the opposite effects.In addition,inhibition of XIAP and NF-κB abrogated the HBXIP overexpression induced radioresistization and increased cell apoptosis(25.8%augment for siRNA XIAP and 28.1%for NF-κB in MDA-MB-231 cells;25.4%augment for siRNA XIAP and 27.2%for NF–κB in MCF-7 cells).Conclusions:HBXIP enhances radioresistance of human breast cancer cells via upregulating XIAP,and targeting the HBXIP–NF–κB-XIAP pathway may be a potentially effective strategy to enhance the efficacy of radiotherapy for human breast cancer.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is causing a high mortality rate due to the lack of efficient early prognosis markers and suitable therapeutic regimens.The prognostic role of genes responsible for t...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is causing a high mortality rate due to the lack of efficient early prognosis markers and suitable therapeutic regimens.The prognostic role of genes responsible for the acquisition of radioresistance in ESCC has not been fully elucidated.AIM To establish a prognostic model by studying gene expression patterns pertinent to radioresistance in ESCC patients.METHODS Datasets were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases.The edgeR,a Bioconductor package,was used to analyze mRNA expression between different groups.We screened genes specifically responsible for radioresistance to estimate overall survival.Pearson correlation analysis was performed to confirm whether the expression of those genes correlated with each other.Genes contributing to radioresistance and overall survival were assessed by the multivariate Cox regression model through the calculation ofβi and risk score using the following formula:∑^(n)_(i=1)βi×PSI.RESULTS We identified three prognostic mRNAs(cathepsin S[CTSS],cluster of differentiation 180[CD180],and SLP adapter and CSK-interacting membrane protein[SCIMP])indicative of radioresistance.The expression of the three identified mRNAs was related to each other(r>0.70 and P<0.05).As to 1-year and 3-year overall survival prediction,the area under the time-dependent receiver operating characteristic curve of the signature consisting of the three mRNAs was 0.716 and 0.841,respectively.When stratifying patients based on the risk score derived from the signature,the high-risk group exhibited a higher death risk and shorter survival time than the low-risk group(P<0.0001).Overall survival of the low-risk patients was significantly better than that of the highrisk patients(P=0.018).CONCLUSION We have developed a novel three-gene prognostic signature consisting of CTSS,CD180,and SCIMO for ESCC,which may facilitate the prediction of early prognosis of this malignancy.展开更多
Cholesterol is a lipid that is an essential component of the membrane structure in mammals.Cholesterol homeostasis regulates vital activities of individual cells and governs the overall function of the mammalian body....Cholesterol is a lipid that is an essential component of the membrane structure in mammals.Cholesterol homeostasis regulates vital activities of individual cells and governs the overall function of the mammalian body.Cholesterol is mainly obtained through the biosynthesis of endogenous cholesterol and the intake of exogenous cholesterol.Cholesterol metabolism in tumor cells is abnormally active,and cholesterol and its metabolites(precursors and derivatives)play important roles in cancer proliferation,survival,invasion,metastasis,and the resistance to radiation.Preclinical studies have indicated that blocking cholesterol synthesis and uptake can reduce tumor progression and improve the response to anticancer treatment.Therapeutic strategies that target cholesterol synthesis,reduce plasma cholesterol levels,and prevent cholesterol esterification represent promising ways to improve the clinical outcome of cancer patients.展开更多
Objective:Our aim was to test the hypothesis that fatty acid synthase(FASN)expression contributes to radioresistance of nasopharyngeal carcinoma(NPC)cells and that inhibiting FASN enhances radiosensitivity.Methods:Tar...Objective:Our aim was to test the hypothesis that fatty acid synthase(FASN)expression contributes to radioresistance of nasopharyngeal carcinoma(NPC)cells and that inhibiting FASN enhances radiosensitivity.Methods:Targeting FASN using epigallocatechin gallate(EGCG)or RNA interference in NPC cell lines that overexpress endogenous FASN was performed to determine their effects on cellular response to radiationin vitro using MTT and colony formation assays,andin vivo using xenograft animal models.Western blot,immunohistochemistry,real-time PCR arrays,and real-time RT-PCR were used to determine the relationship between FASN and frizzled class receptor 10(FZD10)expression.FZD10 knockdown and overexpression were used to determine its role in mediating FASN function in cellular response to radiation.Immunohistochemical staining was used to determine FASN and FZD10 expressions in human NPC tissues,followed by analysis of their association with the overall survival of patients.Results:FASN knockdown or inhibition significantly enhanced radiosensitivity of NPC cells,bothin vitro andin vivo.There was a positive association between FASN and FZD10 expression in NPC cell lines grown as monolayers or xenografts,as well as human tissues.FASN knockdown reduced FZD10 expression,and rescue of FZD10 expression abolished FASN knockdown-induced enhancement of radiosensitivity.FASN and FZD10 were both negatively associated with overall survival of NPC patients.Conclusions:FASN contributes to radioresistance,possiblyvia FZD10 in NPC cells.Both FZD10 and FASN expressions were associated with poor outcomes of NPC patients.EGCG may sensitize radioresistance by inhibiting FASN and may possibly be developed as a radiosensitizer for better treatment of NPCs.展开更多
Ionizing radiation (IR) is the most common treatment used to control localized primary prostate cancer (PC). However, for a significant number of patients, radiotherapy fails to adequately control the tumor. Thus, a m...Ionizing radiation (IR) is the most common treatment used to control localized primary prostate cancer (PC). However, for a significant number of patients, radiotherapy fails to adequately control the tumor. Thus, a main clinical problem today is the lack of a specific marker that may be used to predict the treatment outcome and to identify prostate cancer patients who are unlikely to respond to radiation therapy. In this study, we used human PC xenografts with predetermined radioresistant/sensitive phenotypes, and gene expression microarrays, correlated their specific transcripttional profiles with response to radiation. Employing unsupervised two-way hierarchical clustering, we identified four gene clusters displaying different expression patterns. Two clusters showed higher expression levels in the resistant xenografts and the other two clusters showed higher expression levels in the sensitive xenografts. Expression levels of 113 genes differed by at least 3 fold between sensitive and resistant xenografts. These genes represent members of several cellular pathways, some of which are known to be associated with response to radiation. All or several of these genes could serve as predictive tools to determine at biopsy the expected response of a particular tumor to radiotherapy. Indeed, the profiles we identified enabled us to predict the degree of radiosensitivity of a panel of established PC cell lines. Importantly, irradiation of the PC xenografts did not induce any significant changes in gene expression, regardless of their susceptibility phenotype. These data strongly support the first of two models: a: a random effect of irradiation on a homogeneous population of cells, rather than b: of a tumor comprised of a mixture of radioresistant and radiosensitive cell subpopulations. Our findings imply that each of the radio-phenotypes represents different intrinsic characteristics that affect the ability of a tumor to survive radiotherapy.展开更多
To elucidate the molecular mechanisms underlying cellular radioresistance, clinically relevant radioresistant cell lines were established via long-term exposure to X-rays with stepwise dose escalation. Established cel...To elucidate the molecular mechanisms underlying cellular radioresistance, clinically relevant radioresistant cell lines were established via long-term exposure to X-rays with stepwise dose escalation. Established cells continue to proliferate despite exposure to 2 Gy X-rays/day for more than 30 days, a standard protocol in cancer radiotherapy. DNA repair fidelity in radioresistant and the parental cells by evaluating the mutation frequency at the hypoxanthine phosphoribosyltransferase (HPRT) locus after exposure to X-rays was determined. Mutation spectrum at the HPRT locus was examined by multiplex polymerase chain reaction. Rejoining kinetics of X-ray-induced DNA double strand breaks (dsbs) was evaluated by the detection of phosphorylated histone H2AX (γH2AX) after X-irradiation. The fold increase in the HPRT mutation frequency due to acute radiation was similar between radioresistant and the parental cell lines. However, fractionated radiation (FR) consisting of 2 Gy X-rays/day increased the mutation frequency at the HPRT locus in parental but not in radioresistant cells. Analysis of the FR-induced mutations at the HPRT locus revealed a high frequency of deletion mutations (>70%) in parental but not in radioresistant cells. As assessed by γH2AX immunostaining, DNA dsbs induced by acute exposure to 10 Gy of X-rays were repaired to the control level within 7 days in radioresistant but not in the parental cells. Moreover, 2 Gy × 5 FR increased the number of γH2AX-positive cells in parental cultures but not in radioresistant cultures. DNA dsbs induced by 2 Gy/day FR are repaired with fidelity in radioresistant but not in parental cells.展开更多
Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation ...Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer,including lung cancer,colorectal cancer,and breast cancer.Alteration of Aurora-A impacts multiple cancer hallmarks,especially,immortalization,energy metabolism,immune escape and cell death resistance which are involved in cancer progression and resistance.This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance,including chemoresistance(taxanes,cisplatin,cyclophosphamide),targeted therapy resistance(osimertinib,imatinib,sorafenib,etc.),endocrine therapy resistance(tamoxifen,fulvestrant) and radioresistance.Specifically,the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair,feedback activation bypass pathways,resistance to apoptosis,necroptosis and autophagy,metastasis,and stemness.Noticeably,our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1,ARID1A and MYC gene mutation tumors,and potential synergistic strategy for m TOR,PAK1,MDM2,MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase.In addition,we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.展开更多
Objective:To investigate the mechanism of p53-induced gene 3(PIG3)-regulation of radioresistance in human non-small cell lung cancer(NSCLC)cells,in order to explore new biomarkers and therapeutic targets to combat rad...Objective:To investigate the mechanism of p53-induced gene 3(PIG3)-regulation of radioresistance in human non-small cell lung cancer(NSCLC)cells,in order to explore new biomarkers and therapeutic targets to combat radioresistance and improve the 5-year survival rate.Methods:The PIG3 gene was knocked down in A549 cells using siRNA,and was overexpressed in H1299 cells using a PIG3 expression plasmid.After confirming PIG3 knockdown and overexpression through the Western blot analysis,the radiosensitivity,DNA damage,cell cycle distribution,and apoptosis in these cells were analyzed using colony formation assay,immunofluorescence staining forγH2AX,and flow cytometry,respectively.Results:PIG3 silencing markedly increased the radiosensitivity of NSCLC cells,with radiosensitization ratios of 1.12 and 1.25.Compared with the corresponding negative control,PIG3 knockdown significantly enhanced G2/M phase arrest(siNC:26.12±2.50,siPIG3#1:34.98±4.19,siPIG3#2:37.79±3.53,P<0.05),promoted radiation-induced apoptosis(siNC:14.61±1.85,siPIG3#1:17.26±1.14,siPIG3#2:20.70±2.04,P<0.05),and reduced the number ofγ-H2AX foci 0.5,1,and 2 h after radiation(P<0.05).Conversely,PIG3 overexpression markedly decreased the radiosensitivity of NSCLC cells,as evidenced by the reduction of G2/M phase arrest(NC:33.18±2.11 vs.PIG3:24.21±3.09,P<0.05)and apoptosis(NC:15.49±0.56 vs.PIG3:12.79±0.29,P<0.05),and increased DNA damage(P<0.05).Conclusions:PIG3 downregulation increases the radiosensitivity of NSCLC cells,and PIG3-upregulation leads to the progression in radioresistance.Therefore,PIG3 is a potential target for radiotherapy for NSCLC.展开更多
Radiotherapy(RT)mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death(ICD),which releases damaged-associated molecular patterns and generates“eat me”sig...Radiotherapy(RT)mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death(ICD),which releases damaged-associated molecular patterns and generates“eat me”signals for the innate immune system to modulate the immunogenicity.However,tumor hypoxia significantly reduces the therapeutic efficacy of RT and hampers its mediation of ICD induction.Herein,Au@Bi_(2)Te_(3)-polyethylene glycol(PEG)was rationally constructed as theranostic nanozymes for mild photothermal therapy,tumor hypoxia modulation,and RT adjuvant cancer immunotherapy.The tumor-specific production of oxygen could not only augment the effects of RT by enhanced reactive oxygen species(ROS)generation,but also reduce hypoxia-related cytokines and downregulate programmed cell death-ligand 1(PD-L1)to unleash immune-enhancing T cells.Moreover,Au@Bi_(2)Te_(3)-PEG could act as an immune-blocking inhibitor by efficient ICD induction with the combination of mild-photothermal therapy+RT to inhibit the tumor immune escape and improve antitumor immune response.Increased amounts of CD^(4+) and CD^(8+) Tcells and elevated levels of cytokines could be observed that eventually led to effective post-medication inhibition of primary and abscopal tumors.Spectral computed tomography/photoacoustic imaging allowed noninvasive and real-time tracking of nanoparticle(NP)accumulation and oxygenation status at tumor sites.Collectively,Au@Bi_(2)Te_(3)-PEG NPs could serve as effective theranostic nanoregulators with remarkable synergistic mildphotothermal/RT/immunotherapy effects that helped reshape the immune microenvironment and had remarkable molecular imaging properties.展开更多
基金Supported by Natural Science Foundation of Shandong Province,China,No.ZR2012HQ032China Postdoctoral Science Foundation funded project,No.2013M531614
文摘AIM:To investigate the association between nuclearβ-catenin overexpression in rectal adenocarcinoma and radioresistance.METHODS:A retrospective analysis was conducted.The analysis involved 136 patients with locally advanced rectal adenocarcinoma who underwent shortcourse preoperative radiotherapy and radical resection.The expression ofβ-catenin in both pretreatment biopsy specimens and resected primary tumor tissues was examined by immunohistochemistry.The correlation ofβ-catenin expression with radioresistance was evaluated using the tumor regression grading(TRG)system.The relationship betweenβ-catenin expression and clinicopathological characteristics was also analyzed.Univariate and logistic multivariate regression analyses were adopted to determine the independent factors of radioresistance.RESULTS:Nuclearβ-catenin overexpression was more evident in radioresistant rectal adenocarcinoma than in radiosensitive rectal adenocarcinoma(57.6%vs 16.7%,P<0.001).Nuclearβ-catenin was overexpressed in favor of poor TRG(≤2),whereas membraneβ-catenin was expressed in favor of good TRG(≥3).Nuclearβ-catenin expression in tumor cell differentiation(P=0.018),lymph node metastasis(P=0.022),and TRG(P<0.001)showed significant differences.Univariate analyses demonstrated that radioresistance is associated with nuclearβ-catenin overexpression(P<0.001).In addition,logistic multivariate regression analysis indicated that only three factors,namely,tumor size(P<0.001),tumor cell differentiation(P<0.001),and nuclearβ-catenin overexpression(P<0.001),are associated with radioresistance.By using radioresistance as a prediction target,nuclearβ-catenin-based prediction alone achieved 83%accuracy,65%sensitivity,and88%specificity.CONCLUSION:Nuclearβ-catenin overexpression may be a valuable candidate to predict the response of rectal adenocarcinoma to preoperative radiotherapy.
文摘Hepatocellular carcinoma(HCC), one of the most common cancers in the world, is characterized by poor prognosis and recurrence after resection. Its prevalence is highest in developing countries, particularly where there is high incidence of hepatitis B virus infection. Several curative treatments are available for early stage HCC; however, these options are not available for advanced disease. New techniques allowing the specific delivery of high-dose radiotherapy enable their use in the treatment of HCC, which has been avoided in the past due to low hepatic tolerance for radiation. This presents a new challenge—the development of resistance to radiotherapy and subsequent disease recurrence. Recently, the mechanisms controlling radioresistance have begun to be elucidated. Understanding the molecular basis of radioresistance is key to developing new strategies with better treatment response and increased patient survival.
文摘We present evidence here that abundantly expressed b-catenin-triggered NF-kB-dependent upregulation of inducible nitric oxide synthase(iNOS) found in hepatoma Mahlavu cells (RT-resistant variant designated as RR-Mal), but not in Hep 3B cells (RT-sensitive variant designated as RS-3B) is a key element contribrting to the radioresisitance through the activation of two prominent radioprotective pathways. First, high iNOS expression found in RR-Mal, but not in RS-3B cells was found to perturb calcium homeostasis that triggered ER stress response leading to the overproduction of ER chaperone GRP-78 via robust generation of cleaved ATF-6a (50 kDa) subunits and their nuclear translocation. Meanwhile, both abundantly expressed NF-κB and COX-2 found in RR-Mal cells could also provoke an increased production of PGE2 resulting in robust production of Bcl-2. Interestingly, when RR-Mal cells were treated with PDTC (a NF-κB inhibitor) or celecoxib (a COX-2 inhibitor), a concentration-dependent downregulation of Bcl-2 could be demonstrated implying that Bcl-2 overexpression was indeed mediated through NF-κB/Cox-2/PGE2 pathway. Importantly, we also unveiled that siRNA-mediated silencing of survivin in RR-Mal cells could result in a concomitant downregulation of GRP-78 due to a severe inhibition of ATF-6a (50 kDa) expression. Taken together, our data demonstrate that constitutively overexpressed b-catenin/NF-κB/iNOS and NF-κB/COX-2/PGE2 pathways that overproducing GRP-78, survivin and Bcl-2 expressions are responsible for radioresistance acquisition in RR-Mal cells. Thus, both pathways could be served as potential targets for overcoming radioresistance.
基金Key Program of National Natural Science Foundation of China(U1432248)
文摘Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer, which is the leading cause of death in lung cancer patient. Routine treatment of NSCLC cannot effectively change the survival rate of patients, one important reason is the increased radioresistance of tumor cells after conventional radiotherapy.
文摘The molecular mechanisms of radioresistance of manganese ssuperoxide dismutase (MnSOD) was investigated in thisstudy. We assayed cell necrocis and apoptosis induced by ionizing radiation. Furthermore, the possible roles of oncogenes bc1-2and p53 mRNA expression in MnSOD gene-transfected cells were for investigated. me results showed that 10 Gy X-ray could induce the expression of bc1-2 mRNA and suppress p53 mRNA expression in sense MnSOD transfected cells, whereas Bc1-2 mRNAexpression did not change and p53 mRNA expression increased in antisense MnSOD transfected cells. It is suggested that Bc1-2 isrequired for the radioresistance of MnSOD and the status of p53 play a role in radiation-induced cell death.
基金supported by National Research Foundation of Korea grant funded by the Korea government(MSIT)(2023R1A2C2004510)Korea Basic Science Institute(National Research Facilities and Equipment Center)grant(2020R1A6C101A191)of the Ministry of Education(Korea)the BK21 FOUR Program(Graduate School Innovation)of Sungkyunkwan University.
文摘Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.
基金funded by Deutsche Forschungsgemeinschaft(DFG,GermanResearch Foundation)under Germany's Excellence Strategy EXC2151390873048 of which E.B.,G.H.,and M.S.are memberssupported by other grants of DFG,including Project-ID 369799452 TRR237 to E.B.,G.H.,and M.S.,Project-ID 397484323 TRR259 to G.H.,GRK 2168 to E.B.and M.S.,and DFG SCHL1930/1-2+1 种基金funded by the Deutsche Krebshilfe through a Mildred Scheel Nachwuchszentrum(70113307)the recipient of a PhD scholarship from Bayer Pharma AG(40860128).
文摘Radiotherapy induces DNA damage,resulting in cell cycle arrest and activation of cell-intrinsic death pathways.However,the radioresistance of some tumour entities such as malignant melanoma limits its clinical application.The innate immune sensing receptor retinoic acid-inducible gene I(RIG-I)is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma.To date,the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated.Here,we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo.Transcriptome analysis pointed to a central role for p53,which was confirmed using p53^(-/-)B16 cells.In vivo,the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53^(-/-)B16 tumours,while the antitumoural response to RIG-I stimulation alone was maintained.Our results identify p53 as a pivotal checkpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death.Thus,the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway,such as melanoma.
基金This study is supported by the National Natural Science Foundation of China(No.81672972).
文摘Small cell lung cancer(SCLC)is a highly aggressive tumor type for which limited therapeutic progress has been made.Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment,but most patients with SCLC acquire therapeutic resistance.Given the need for more effective therapies,better elucidation of the molecular pathogenesis of SCLC is imperative.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors.This pathway is an important regulator of cancer cell glucose metabolism,and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC.Glucose metabolism has three main branches-aerobic glycolysis,oxidative phosphorylation,and the pentose phosphate pathway-involved in radioresistance.The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1(HIF-1)signaling.The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance,including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway.This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway,hypoxia,and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.
基金supported by the National Natural Science Foundation of China(No.81971731,82001963,82172082)PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(No.3332020058)+1 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2018PT35031)the Natural Science Fund for Distinguished Young Scholars of Tianjin(18JCJQJC47300)and the CAMS Innovation Fund for Medical Sciences(2021-I2M042).
文摘Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application,which is mainly caused by the aggravation of immunosuppressive tumor microenvironment(ITM).Especially tumor-associated macrophages(TAMs)usually display the tumor-promoting M2 phenotype during high-dose fractional radiotherapy mediating radiotherapy resistance.Herein,the toll like receptor agonist TLR7/8a was conjugated with radiosensitive peptide hydrogel(Smac-TLR7/8 hydrogel)to regulate TAMs repolarization from M2 type into M1 type,thus modulating the ITM and overcoming the radioresistance.The Smac-TLR7/8 hydrogel was fabricated through self-assembly with nanofibrous morphology,porous structure and excellent biocompatibility.Uponγ-ray radiation,Smac-TLR7/8 hydrogel effectively polarized the macrophages into M1 type.Notably,combined with radiotherapy,TAMs repolarization regulated by Smac-TLR7/8 hydrogel could increase tumor necrosis factor secretion,activate antitumor immune response and effectively inhibit tumor growth.Moreover,TAMs repolarization rebuilt the ITM and elicited the immunogenic phenotypes in solid tumors,thus enhanced the PD1-blockade efficacy through increasing tumor infiltrating lymphocytes(TILs)and decreasing Treg cells in two different immune activity tumor mice models.Overall,this study substantiated that recruiting and repolarization of TAMs were critical in eliciting antitumor immune response and overcoming radioresistance,thus improving the efficacy of radiotherapy and immunotherapy.
基金This study is supported by grants from the National Natural Science Foundation of China(Grant No.31530085,31870847,U1803124).
文摘Hypoxia is a big roadblock for cancer radiotherapy,in which the hypoxia-inducible factor(HIF-1)creates a microenvironment and cancer cells’intrinsic signaling networks conferring radioresistance to cancers.HIF-1 is a heterodimeric transcription factor HIF-1α/HIF-1β,that regulates the transcription of a broad range of downstream genes possessing an E-box-like hypoxia response element(HRE).The expression of HIF-1αis oxygensensitive while HIF-1βis constitutively expressed.In addition to hypoxia,ionizing radiation can also induce the expression of HIF-1α.The HIF-1 modulates a set of signaling pathways to cause profound effects on the response of cancer to radiotherapy,including radiation-induced DNA damage response(DDR),vasculogenesis and glucose metabolism reprograming,epithelial mesenchymal transition(EMT),etc.In this review,our aim is to summarize the current knowledge about the role and the related signal pathways of HIF-1 in association with the resistance of cancers to radiotherapy.Targeting HIF-1 and its signal pathways is a promising strategy for sensitization of cancers to radiotherapy.
基金Supported by the National Basic Research Program of China (Grant No. 2004CB19604)the National Natural Science Foundation of China (Grant No. 30330020)the National Science fund for Distinguished Young Scholars (Grant No. 30425038)
文摘The conclusion based on transmission electron microscopy, "the tightly packed ring-like nucleoid of the Deinococcus radiodurans R1 is a key to radioresistance", has instigated lots of debates. In this study, according to the previous research of PprI’s crucial role in radioresistance of D. radiodurans, we have attempted to examine and compare the nucleoid morphology differences among wild-type D. ra-diodurans R1 strain, pprI function-deficient mutant (YR1), and pprI function-complementary strains (YR1001, YR1002, and YR1004) before and after exposure to ionizing irradiation. Fluorescence mi-croscopy images indicate: (1) the majority of nucleoid structures in radioresistant strain R1 cells ex-hibit the tightly packed ring-like morphology, while the pprI function-deficient mutant YR1 cells carrying predominate ring-like structure represent high sensitivity to irradiation; (2) as an extreme radioresistant strain similar to wild-type R1, pprI completely function-complementary strain YR1001 almost displays the loose and irregular nucleoid morphologies. On the other hand, another radioresistant pprI partly function-complementary strain YR1002’s nucleiods exhibit about 60% ring-like structure; (3) a PprI C-terminal deletion strain YR1004 consisting of approximately 60% of ring-like nucleoid is very sensi-tive to radiation. Therefore, our present experiments do not support the conclusion that the ring-like nucleoid of D. radiodurans does play a key role in radioresistance.
基金This study was supported by the grants from the National Natural Science Foundation of China (No.31770910 and No.81730086).
文摘Objective:Hepatitis B X-interacting protein(HBXIP)plays an important role in breast tumorigenesis,tumor growth and metastasis,but its functional contribution in radioresistance remains poorly understood.As radiotherapy served as an essential adjuvant treatment,uncovering the role of HBXIP as well as its downstream molecular XIAP in radioresistance could benefit for the development of individual therapy strategy.Methods:Immunohistochemistry of 42 breast cancer tissue samples and Western blot analysis of proteins from MCF-7 and MDA-MB-231 cells exposed to fractioned doses(γ-rays)were used to identify the expression of HBXIP/XIAP in breast cancer.To verify the radioresistance effects and potential mechanism,the cells were treated with designed pCMV and siRNA of targeting genes,and then measured with MTT assay,clonogenic survival assay and flow cytometry.Furthermore,a subcutaneous xenotransplanted tumor model of breast cancer was established in nude mice to validate the radioresistization effect of HBXIP in vivo.Results:HBXIP and XIAP expression levels in breast cancer tissues were positively correlated with chemoradiotherapy resistance of breast cancer.Overexpression of HBXIP could desensitize MCF-7 and MDA-MB-231 cells to irradiation by inhibiting radiation-induced cell apoptosis,and knockdown of HBXIP in these cells had the converse response.Moreover,up-regulation of HBXIP resulted in the increase of XIAP and NF-κB levels in vitro and in vivo,while down-regulation of HBXIP led to the opposite effects.In addition,inhibition of XIAP and NF-κB abrogated the HBXIP overexpression induced radioresistization and increased cell apoptosis(25.8%augment for siRNA XIAP and 28.1%for NF-κB in MDA-MB-231 cells;25.4%augment for siRNA XIAP and 27.2%for NF–κB in MCF-7 cells).Conclusions:HBXIP enhances radioresistance of human breast cancer cells via upregulating XIAP,and targeting the HBXIP–NF–κB-XIAP pathway may be a potentially effective strategy to enhance the efficacy of radiotherapy for human breast cancer.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is causing a high mortality rate due to the lack of efficient early prognosis markers and suitable therapeutic regimens.The prognostic role of genes responsible for the acquisition of radioresistance in ESCC has not been fully elucidated.AIM To establish a prognostic model by studying gene expression patterns pertinent to radioresistance in ESCC patients.METHODS Datasets were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases.The edgeR,a Bioconductor package,was used to analyze mRNA expression between different groups.We screened genes specifically responsible for radioresistance to estimate overall survival.Pearson correlation analysis was performed to confirm whether the expression of those genes correlated with each other.Genes contributing to radioresistance and overall survival were assessed by the multivariate Cox regression model through the calculation ofβi and risk score using the following formula:∑^(n)_(i=1)βi×PSI.RESULTS We identified three prognostic mRNAs(cathepsin S[CTSS],cluster of differentiation 180[CD180],and SLP adapter and CSK-interacting membrane protein[SCIMP])indicative of radioresistance.The expression of the three identified mRNAs was related to each other(r>0.70 and P<0.05).As to 1-year and 3-year overall survival prediction,the area under the time-dependent receiver operating characteristic curve of the signature consisting of the three mRNAs was 0.716 and 0.841,respectively.When stratifying patients based on the risk score derived from the signature,the high-risk group exhibited a higher death risk and shorter survival time than the low-risk group(P<0.0001).Overall survival of the low-risk patients was significantly better than that of the highrisk patients(P=0.018).CONCLUSION We have developed a novel three-gene prognostic signature consisting of CTSS,CD180,and SCIMO for ESCC,which may facilitate the prediction of early prognosis of this malignancy.
基金supported by grants from the Project of Sichuan Science and Technology Department(No.2021YJ0010)the Sichuan Natural Science Foundation(No.2023NSFC0712).
文摘Cholesterol is a lipid that is an essential component of the membrane structure in mammals.Cholesterol homeostasis regulates vital activities of individual cells and governs the overall function of the mammalian body.Cholesterol is mainly obtained through the biosynthesis of endogenous cholesterol and the intake of exogenous cholesterol.Cholesterol metabolism in tumor cells is abnormally active,and cholesterol and its metabolites(precursors and derivatives)play important roles in cancer proliferation,survival,invasion,metastasis,and the resistance to radiation.Preclinical studies have indicated that blocking cholesterol synthesis and uptake can reduce tumor progression and improve the response to anticancer treatment.Therapeutic strategies that target cholesterol synthesis,reduce plasma cholesterol levels,and prevent cholesterol esterification represent promising ways to improve the clinical outcome of cancer patients.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81572588,81872147)Shantou University Medical College Clinical Trial Uplift Program(Grant No.201423)+4 种基金the Medical Scientific Research Foundation of Guangdong Province,China(Grant No.B2018222)the Traditional Chinese Medicine Research Project from Traditional Chinese Medicine Bureau of Guangdong Province(Grant No.20191182)the Youth Research Grant from Shantou University Medical College Cancer Hospital(Grant No.2018A001,2018A008)the key Project of Science and Technology of Shantou[Grant No.(2018)37]and the Natural Science Foundation of Guangdong Province of China(Grant No.2020A1515010094).
文摘Objective:Our aim was to test the hypothesis that fatty acid synthase(FASN)expression contributes to radioresistance of nasopharyngeal carcinoma(NPC)cells and that inhibiting FASN enhances radiosensitivity.Methods:Targeting FASN using epigallocatechin gallate(EGCG)or RNA interference in NPC cell lines that overexpress endogenous FASN was performed to determine their effects on cellular response to radiationin vitro using MTT and colony formation assays,andin vivo using xenograft animal models.Western blot,immunohistochemistry,real-time PCR arrays,and real-time RT-PCR were used to determine the relationship between FASN and frizzled class receptor 10(FZD10)expression.FZD10 knockdown and overexpression were used to determine its role in mediating FASN function in cellular response to radiation.Immunohistochemical staining was used to determine FASN and FZD10 expressions in human NPC tissues,followed by analysis of their association with the overall survival of patients.Results:FASN knockdown or inhibition significantly enhanced radiosensitivity of NPC cells,bothin vitro andin vivo.There was a positive association between FASN and FZD10 expression in NPC cell lines grown as monolayers or xenografts,as well as human tissues.FASN knockdown reduced FZD10 expression,and rescue of FZD10 expression abolished FASN knockdown-induced enhancement of radiosensitivity.FASN and FZD10 were both negatively associated with overall survival of NPC patients.Conclusions:FASN contributes to radioresistance,possiblyvia FZD10 in NPC cells.Both FZD10 and FASN expressions were associated with poor outcomes of NPC patients.EGCG may sensitize radioresistance by inhibiting FASN and may possibly be developed as a radiosensitizer for better treatment of NPCs.
文摘Ionizing radiation (IR) is the most common treatment used to control localized primary prostate cancer (PC). However, for a significant number of patients, radiotherapy fails to adequately control the tumor. Thus, a main clinical problem today is the lack of a specific marker that may be used to predict the treatment outcome and to identify prostate cancer patients who are unlikely to respond to radiation therapy. In this study, we used human PC xenografts with predetermined radioresistant/sensitive phenotypes, and gene expression microarrays, correlated their specific transcripttional profiles with response to radiation. Employing unsupervised two-way hierarchical clustering, we identified four gene clusters displaying different expression patterns. Two clusters showed higher expression levels in the resistant xenografts and the other two clusters showed higher expression levels in the sensitive xenografts. Expression levels of 113 genes differed by at least 3 fold between sensitive and resistant xenografts. These genes represent members of several cellular pathways, some of which are known to be associated with response to radiation. All or several of these genes could serve as predictive tools to determine at biopsy the expected response of a particular tumor to radiotherapy. Indeed, the profiles we identified enabled us to predict the degree of radiosensitivity of a panel of established PC cell lines. Importantly, irradiation of the PC xenografts did not induce any significant changes in gene expression, regardless of their susceptibility phenotype. These data strongly support the first of two models: a: a random effect of irradiation on a homogeneous population of cells, rather than b: of a tumor comprised of a mixture of radioresistant and radiosensitive cell subpopulations. Our findings imply that each of the radio-phenotypes represents different intrinsic characteristics that affect the ability of a tumor to survive radiotherapy.
文摘To elucidate the molecular mechanisms underlying cellular radioresistance, clinically relevant radioresistant cell lines were established via long-term exposure to X-rays with stepwise dose escalation. Established cells continue to proliferate despite exposure to 2 Gy X-rays/day for more than 30 days, a standard protocol in cancer radiotherapy. DNA repair fidelity in radioresistant and the parental cells by evaluating the mutation frequency at the hypoxanthine phosphoribosyltransferase (HPRT) locus after exposure to X-rays was determined. Mutation spectrum at the HPRT locus was examined by multiplex polymerase chain reaction. Rejoining kinetics of X-ray-induced DNA double strand breaks (dsbs) was evaluated by the detection of phosphorylated histone H2AX (γH2AX) after X-irradiation. The fold increase in the HPRT mutation frequency due to acute radiation was similar between radioresistant and the parental cell lines. However, fractionated radiation (FR) consisting of 2 Gy X-rays/day increased the mutation frequency at the HPRT locus in parental but not in radioresistant cells. Analysis of the FR-induced mutations at the HPRT locus revealed a high frequency of deletion mutations (>70%) in parental but not in radioresistant cells. As assessed by γH2AX immunostaining, DNA dsbs induced by acute exposure to 10 Gy of X-rays were repaired to the control level within 7 days in radioresistant but not in the parental cells. Moreover, 2 Gy × 5 FR increased the number of γH2AX-positive cells in parental cultures but not in radioresistant cultures. DNA dsbs induced by 2 Gy/day FR are repaired with fidelity in radioresistant but not in parental cells.
基金supported by the Natural Science Foundation of Hebei Province(No.H2020209284,China,Dayong Zheng)Scientific Research Foundation of Higher Education Institutions of Hebei Province(No.QN2021120,Dayong Zheng)+1 种基金Department of Science and Technology of Liaoning province(No.2020-MS-225,China,Jun Li)the Montefiore Einstein Cancer Center grant(NCI P30CA013330,USA,Edward Chu)。
文摘Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer,including lung cancer,colorectal cancer,and breast cancer.Alteration of Aurora-A impacts multiple cancer hallmarks,especially,immortalization,energy metabolism,immune escape and cell death resistance which are involved in cancer progression and resistance.This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance,including chemoresistance(taxanes,cisplatin,cyclophosphamide),targeted therapy resistance(osimertinib,imatinib,sorafenib,etc.),endocrine therapy resistance(tamoxifen,fulvestrant) and radioresistance.Specifically,the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair,feedback activation bypass pathways,resistance to apoptosis,necroptosis and autophagy,metastasis,and stemness.Noticeably,our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1,ARID1A and MYC gene mutation tumors,and potential synergistic strategy for m TOR,PAK1,MDM2,MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase.In addition,we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.
基金This research was funded by the National Natural Science Foundation of China(81673091,31300694).
文摘Objective:To investigate the mechanism of p53-induced gene 3(PIG3)-regulation of radioresistance in human non-small cell lung cancer(NSCLC)cells,in order to explore new biomarkers and therapeutic targets to combat radioresistance and improve the 5-year survival rate.Methods:The PIG3 gene was knocked down in A549 cells using siRNA,and was overexpressed in H1299 cells using a PIG3 expression plasmid.After confirming PIG3 knockdown and overexpression through the Western blot analysis,the radiosensitivity,DNA damage,cell cycle distribution,and apoptosis in these cells were analyzed using colony formation assay,immunofluorescence staining forγH2AX,and flow cytometry,respectively.Results:PIG3 silencing markedly increased the radiosensitivity of NSCLC cells,with radiosensitization ratios of 1.12 and 1.25.Compared with the corresponding negative control,PIG3 knockdown significantly enhanced G2/M phase arrest(siNC:26.12±2.50,siPIG3#1:34.98±4.19,siPIG3#2:37.79±3.53,P<0.05),promoted radiation-induced apoptosis(siNC:14.61±1.85,siPIG3#1:17.26±1.14,siPIG3#2:20.70±2.04,P<0.05),and reduced the number ofγ-H2AX foci 0.5,1,and 2 h after radiation(P<0.05).Conversely,PIG3 overexpression markedly decreased the radiosensitivity of NSCLC cells,as evidenced by the reduction of G2/M phase arrest(NC:33.18±2.11 vs.PIG3:24.21±3.09,P<0.05)and apoptosis(NC:15.49±0.56 vs.PIG3:12.79±0.29,P<0.05),and increased DNA damage(P<0.05).Conclusions:PIG3 downregulation increases the radiosensitivity of NSCLC cells,and PIG3-upregulation leads to the progression in radioresistance.Therefore,PIG3 is a potential target for radiotherapy for NSCLC.
基金This work was supported by the National Natural Science Foundation of China(Nos.81871334,81801764,82072056,and 51937010)the Guangdong Basic and Applied Basic Research Foundation(Nos.2017A050506011,2018030310343,2020B1515020008,2021A1515012542,and 2021A1515011882)+1 种基金the Medical Scientific Research Foundation of Guangdong Province(No.A2018014)the Pearl River Talented Young Scholar Program(No.2017GC010282).
文摘Radiotherapy(RT)mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death(ICD),which releases damaged-associated molecular patterns and generates“eat me”signals for the innate immune system to modulate the immunogenicity.However,tumor hypoxia significantly reduces the therapeutic efficacy of RT and hampers its mediation of ICD induction.Herein,Au@Bi_(2)Te_(3)-polyethylene glycol(PEG)was rationally constructed as theranostic nanozymes for mild photothermal therapy,tumor hypoxia modulation,and RT adjuvant cancer immunotherapy.The tumor-specific production of oxygen could not only augment the effects of RT by enhanced reactive oxygen species(ROS)generation,but also reduce hypoxia-related cytokines and downregulate programmed cell death-ligand 1(PD-L1)to unleash immune-enhancing T cells.Moreover,Au@Bi_(2)Te_(3)-PEG could act as an immune-blocking inhibitor by efficient ICD induction with the combination of mild-photothermal therapy+RT to inhibit the tumor immune escape and improve antitumor immune response.Increased amounts of CD^(4+) and CD^(8+) Tcells and elevated levels of cytokines could be observed that eventually led to effective post-medication inhibition of primary and abscopal tumors.Spectral computed tomography/photoacoustic imaging allowed noninvasive and real-time tracking of nanoparticle(NP)accumulation and oxygenation status at tumor sites.Collectively,Au@Bi_(2)Te_(3)-PEG NPs could serve as effective theranostic nanoregulators with remarkable synergistic mildphotothermal/RT/immunotherapy effects that helped reshape the immune microenvironment and had remarkable molecular imaging properties.
