AIM: To investigate the effect of Girdin knockdown on the chemosensitivity of colorectal cancer cells to oxaliplatin and the possible mechanisms involved.METHODS: Four siRNAs targeting Girdin were transfected into the...AIM: To investigate the effect of Girdin knockdown on the chemosensitivity of colorectal cancer cells to oxaliplatin and the possible mechanisms involved.METHODS: Four siRNAs targeting Girdin were transfected into the chemoresistant colorectal cancer cell line DLD1. Real-time polymerase chain reaction(PCR) was employed to assess Girdin mRNA expression and the most effective siRNA was chosen for conversion into shRNA. Then, DLD1 cells were infected with lentiviruses expressing the Girdin shRNA and a scramble control, respectively, and Girdin mRNA and protein expression levels were assessed by real-time PCR and Western blotting. Furthermore, microarray experiments were used to assess global gene expression profile after Girdin suppression in DLD1 cells. Finally, the cytotoxic effect of simultaneous treatment with oxaliplatin and adriamycin(an inhibitor of a significantly downregulated gene after Girdin suppression in DLD1 cells) was examined by MTT assay.RESULTS: The most effective siRNA suppressed Girdinexpression with an inhibition efficiency of 57%. Compared with the scramble control, DLD1 cells infected with the Girdin shRNA displayed decreased Girdin mRNA and protein levels(P < 0.05), and Girdin knockdown significantly enhanced chemosensitivity to oxaliplatin in colorectal cancer cells(P < 0.05). Microarray data revealed that 381 and 162 genes were upregulated and downregulated in response to Girdin reduction, respectively, with ratios > 1.2 or < 0.8(P < 0.01). Interestingly, TOP2B(DNA topoisomerase 2-β) was downregulated(ratio = 0.78, P = 0.0001) and oxaliplatin/adriamycin combination resulted in increased cell death compared with treatments with individual agents(P < 0.05).CONCLUSION: Girdin knockdown enhances chemosensitivity of colorectal cancer cells to oxaliplatin via TOP2B down-regulation. These findings provide a promising approach to overcome the chemoresistance of colorectal cancer cells.展开更多
Oligodendroglial tumors frequently have deletions ofchromosomal loci on lp and l9q.Loas of heterozygosity(LOH)of chromosome 10 may be a negative prognostic factor.We reviewed 23 patients with oligodendroglial tumors,t...Oligodendroglial tumors frequently have deletions ofchromosomal loci on lp and l9q.Loas of heterozygosity(LOH)of chromosome 10 may be a negative prognostic factor.We reviewed 23 patients with oligodendroglial tumors,toevaluate the frequency of lp and 10q LOH and correlate with clinical outcome.Three loci(DlS402,DlSl 172,MCT118)on lp and 2 loci(Dl0S520 and D10S521)on 10q were analyzed for LOH using PCR techniques.展开更多
Objective:To study the influence of curcumin on chemosensitivity of nephroblastoma cells.Methods:Human nephroblastoma cells line SK-NEP-1 was transplanted to the nude mice subcutaneously to establish the implantation ...Objective:To study the influence of curcumin on chemosensitivity of nephroblastoma cells.Methods:Human nephroblastoma cells line SK-NEP-1 was transplanted to the nude mice subcutaneously to establish the implantation tumor model of human nephroblastoma cells.A total of 30 tumor-bearing mice were divided into three groups of ten randomly.The routine chemotherapy group was given vincristine(0.05 mg/mL·0.2 mL/d) and actinomycin D(15 ng/mL·0.2 mL/d) combined chemotherapy regime.The curcumin chemotherapy group was given the same combined chemotherapy regimens and curcumin(30 mg/kg/d) by intraperitoneal injection.The control group was given normal saline(NS) of the same volume by intraperitoneal injection.Continuous administration would be kept for 4 weeks and 3 days a week.The volumetric changes of every group were recorded.The serum of every group in different time was collected and the VEGF content was detected by ELISA.All mice were cercrificed and the tumor tissues were stripped and weighed after 4 weeks’ treatment.The tumor inhibition rate was calculated.The cell proliferation activity and apoptosis rate were detected by MTT and flow cytometry method.All data were statistically analyzed by SPSS 19.0.Results:The tumor volume,serum VEGF content,tumor inhibition rate,cell proliferation activity and apoptosis rate of routine chemotherapy group and curcumin chemotherapy group had significant differences comparing with the control group(P<0.05) after 4-week’s treatment.The cancer growth of curcumin chemotherapy group was obviously decreased and even tended to shrink comparing with routine chemotherapy group(χ2=15.732,P=0.007).The cell proliferation activity was significantly reduced and the apoptosis rate was significantly higher,(χ~2=9.427,P=0.012)which showing the effect of chemotherapy was enhanced.Conclusions:The chemosensitivity of nephroblastoma cells could be improved by curcumin,then the effect of preoperative adjuvant chemotherapy scheme would be enhanced,the growth of nephroblastoma cells would be inhibited and the surgical risk of nephroblastoma would be reduced.展开更多
Objective: To determine the effects on the cell growth, tumorigenicity and chemosensitivity of p16/CDK4I in human glioma. Methods: p16 gene was transfected into U251 cells by lipofectin. Expression of exogenous p16 ge...Objective: To determine the effects on the cell growth, tumorigenicity and chemosensitivity of p16/CDK4I in human glioma. Methods: p16 gene was transfected into U251 cells by lipofectin. Expression of exogenous p16 gene was confirmed by immunohistochemistry and Northern blot. The effects of exogenous p16 gene on the growth and chemosensitivity to teniposide were examined. Results: Expression of exogenous p16 gene inhibited the growth dramatically in vitro. G1 arrest of tumor cells was observed. However, wt p16-positive U251 was less sensitive than control cell lines and the number of apoptotic cells after chemotherapy was reduced. Conclusion: The expression of exogenous p16 gene could inhibit the growth of glioma. On the other hand, the chemosensitivity to teniposide of p16-positive U251 was decreased.展开更多
Intrahepatic cholangiocarcinoma(ICC)is the second most common liver cancer.Chemotherapy remains the main therapeutic strategy for advanced ICC patients,but chemosensitivity varies individually.Here,we applied cytometr...Intrahepatic cholangiocarcinoma(ICC)is the second most common liver cancer.Chemotherapy remains the main therapeutic strategy for advanced ICC patients,but chemosensitivity varies individually.Here,we applied cytometry by time-of-flight(CyTOF)to establish the immune profile of peripheral blood mononuclear cells(PBMCs)on the single-cell level at indicated time points before,during,and after chemotherapy.Multiplex immunofluorescence staining was applied to examine the spatial distribution of certain immune clusters.Tissue microarrays(TMAs)were used for prognostic evaluation.A total of 20 ICC patients treated with gemcitabine(GEM)were enrolled in our study,including eight cases with good response(R)and 12 cases with non-response(NR).Tremendous changes in PBMC composition,including an increased level of CD4/CD8 double-positive T cells(DPT),were observed after chemotherapy.Patients with higher level of CD4^(+)CD45RO^(+)CXCR3^(+)T cells before treatment had a favorable response to chemotherapy.Our study identified a positive correlation between the percentage of T cell subpopulations and clinical response after chemotherapy,which suggests that it is practical to predict the potential response before treatment by evaluating the proportions of the cell population in PBMCs.展开更多
Objective The aim of the study was to evaluate the role of ATP-based tumor chemosensitivity assay(ATP-TCA) in patients with platinum-resistant recurrent ovarian cancer(PRROC).Methods A total of 43 patients with PRROC ...Objective The aim of the study was to evaluate the role of ATP-based tumor chemosensitivity assay(ATP-TCA) in patients with platinum-resistant recurrent ovarian cancer(PRROC).Methods A total of 43 patients with PRROC who underwent chemotherapy based on the results of ATPTCA in the Cancer Hospital,Chinese Academy of Medical Sciences were included in the present study.As controls,we selected another 43 patients with PRROC who were treated at the physician's discretion within the same time period and had the same clinical characteristics as the patients in the ATP-TCA group.Logrank test and Cox proportional hazards model were adopted for analysis.Results A total of 86 patients were retrospectively analyzed in the present study.Patients were routinely monitored to evaluate the rate of progression-free survival(PFS).The median follow-up time was 13 months.The PFS for the ATP-TCA and control groups was 5 and 3 months,respectively(P = 0.027).Multivariate analysis showed that the type of treatment was an independent prognostic factor for PFS(P = 0.040;HR:0.623;95% CI:0.313–0.973).Subgroup analysis showed that among patients with a treatmentfree interval(TFI) of ≥ 3 months(n = 50),those in the ATP-TCA group had longer PFS than those in the control group(7 vs 4 months,P = 0.010).Meanwhile,the median PFS of patients who underwent ≤ 2 prior chemotherapy regimens(PCR,n = 52) in the ATP-TCA and control groups was 6 months and 4 months,respectively(P = 0.025).Conclusion ATP-TCA-directed chemotherapy might improve the PFS in PRROC.In particular,the survival benefit from ATP-TCA is higher in patients with a TFI of ≥ 3 months or treated with ≤ 2 PCR.展开更多
Objective The aim of the study was to investigate whether colon cancer stem cells induced by epidermal growth factor(EGF) to enter the cell cycle enhanced the chemosensitivity of colon cancer.Methods In vitro,EGF was ...Objective The aim of the study was to investigate whether colon cancer stem cells induced by epidermal growth factor(EGF) to enter the cell cycle enhanced the chemosensitivity of colon cancer.Methods In vitro,EGF was used to stimulate the entry of human colon cancer HCT116 cells into the cell cycle.Before and after treatment with EGF,CD133+ HCT116 cells were collected and flow cytometry was conducted to determine the apoptosis rate based on the 5-Fu and Ki-67 expression rates.The cell cycle distribution of the two groups was also determined.In vivo,a subcutaneous xenograft model of HCT116 human colon cancer cell lines in nude mice was established.The nude mice were divided into two groups and treated with EGF and 5-Fu,respectively.Differences in the growth of implanted tumors revealed the efficiency of cycle-induction combined chemotherapy.Results(1) After EGF stimulation,the S-G2/M proportion of CD133+ HCT116 cells and Ki67 expression were increased,indicating that more cancer stem cells entered the cell cycle and promoted proliferation;(2) After EGF stimulation,CD133+ HCT116 cells showed a higher apoptosis rate induced by 5-Fu.(3) Animal experiments showed that the group subjected to combined treatment with EGF and 5-Fu had smaller tumor sizes compared to the group treated with 5-Fu alone.Conclusion EGF enhanced tumor sensitivity to chemotherapeutic drugs,likely by promoting tumor stem cells to enter the cell cycle.展开更多
Finding effective cancer treatment is a challenge, because the sensitivity of the cancer stems from both intrinsic cellular properties and acquired resistances from prior treatment. Previous research has revealed indi...Finding effective cancer treatment is a challenge, because the sensitivity of the cancer stems from both intrinsic cellular properties and acquired resistances from prior treatment. Previous research has revealed individual protein markers that are significant to chemosensitivity prediction. Our goal is to find correlated protein markers which are collectively significant to chemosensitivity prediction to complement the individual markers already reported. In order to do this, we used the D’ correlation measurement to study the feature selection correlations for chemosensitivity prediction of 118 anticancer agents with putatively known mechanisms of action. Three data-sets on the NCI-60 were utilized in this study: two protein datasets, one previously studied for chemosensitivity prediction and another novel to this topic, and one DNA copy number dataset. To validate our approach, we identified the protein markers that were strongly correlated by our analysis with the individual protein markers found in previous studies. Our feature analysis discovered highly correlated protein marker pairs, based on which we found individual protein markers with medical significance. While some of the markers uncovered were consistent with those previously reported, others were original to this work. Using these marker pairs we were able to further correlate the cellular functions associated with them. As an exploratory analysis, we discovered feature selection correlation patterns between and within different drug mechanisms of action for each of our datasets. In conclusion, the highly correlated protein marker pairs as well as their functions found by our feature analysis are validated by previous studies, and are shown to be medically significant, demonstrating D’ as an effective measurement of correlation in the context of feature selection for the first time.展开更多
Several gene signatures have been identified to build predictors of chemosensitivity for breast cancer. It is crucial to understand how each gene in a signature contributes to the prediction, i.e., to make the predict...Several gene signatures have been identified to build predictors of chemosensitivity for breast cancer. It is crucial to understand how each gene in a signature contributes to the prediction, i.e., to make the prediction model interpretable instead of using it as a black box. We utilized Random Forests (RFs) to build two interpretable predictors of pathologic complete response (pCR) based on two gene signatures. One signature consisted of the top 31 probe sets (27 genes) differentially expressed between pCR and residual disease (RD) chosen from a previous study, and the other consisted of the genes involved in Notch singling pathway (113 genes). Both predictors had a higher accuracy (82% v 76% & 79% v 76%), a higher specificity (91% v 71% & 98% v 71%), and a higher positive predictive value (PPV) (68% v 52% & 73% v 52%)) than the predictor in the previous study. Furthermore, Random Forests were employed to calculate the importance of each gene in the two signatures. Findings of our functional annotation suggested that the important genes identified by the feature selection scheme of Random Forests are of biological significance.展开更多
Various gene signatures of chemosensitivity in breast cancer have been discovered. One previous study employed t-test to find a signature of 31 probe sets (27 genes) from a group of patients who received weekly preope...Various gene signatures of chemosensitivity in breast cancer have been discovered. One previous study employed t-test to find a signature of 31 probe sets (27 genes) from a group of patients who received weekly preoperative chemotherapy. Based on this signature, a 30-probe set diagonal linear discriminant analysis (DLDA-30) classifier of pathologic complete response (pCR) was constructed. In this study, we sought to uncover a signature that is much smaller than the 31 probe sets and yet has enhanced predictive performance. A signature of this nature could inform us what genes are essential in response prediction. Genetic algorithms (GAs) and sparse logistic regression (SLR) were employed to identify two such small signatures. The first had 13 probe sets (10 genes) selected from the 31 probe sets and was used to build a SLR predictor of pCR (SLR-13), and the second had 14 probe sets (14 genes) selected from the genes involved in Notch signaling pathway and was used to develop another SLR predictor of pCR (SLR-Notch-14). The SLR-13 and SLR-Notch-14 had a higher accuracy and a higher positive predictive value than the DLDA-30 with much lower P values, suggesting that our two signatures had their own discriminative power with high statistical significance. The SLR prediction model also suggested the dual role of gene RNUX1 in promoting residual disease (RD) or pCR in breast cancer. Our results demonstrated that the multivariable techniques such as GAs and SLR are effective in finding significant genes in chemosensitivity prediction. They have the advantage of revealing the interacting genes, which might be missed by single variable techniques such as t-test.展开更多
Background: Chemotherapy is a mainstay of tumor therapy, however, it is predominantly applied according to empirically developed recommendations derived from statistical relapse rates occurring years after the treatme...Background: Chemotherapy is a mainstay of tumor therapy, however, it is predominantly applied according to empirically developed recommendations derived from statistical relapse rates occurring years after the treatment in the adjuvant situation and from progression-free interval data in the metastatic situation, without any possibility of individually determining the efficacy in the adjuvant situation and with loss of time and quality of life in the metastatic situation if the drugs chosen are not effective. Here, we present a method to determine the efficiency of chemotherapeutic drugs using tumor cells circulating in blood as the part of the tumor actually available in the patient’s body for chemosensitivity testing. Methodology/Principal Findings: After only red blood cell lysis, omitting any enrichment (analogous to other blood cell enumeration methods, including rare CD34 cells), the white cells comprising the circulating epithelial tumor cells (CETC) are exposed to the drugs in question in different concentrations and for different periods of time. Staining with a fluorescence-labeled anti-epithelial antibody detects both vital and dying tumor cells, distinguishing vital from dying cells through membrane permeability and nuclear staining with propidium iodide. Increasing percentages of dying tumor cells are observed dependent on time and concentration. The sensitivity can vary during therapy and was correlated with decrease or increase in CETC and clinical outcome. Conclusions/Significance: Thus, we are able to show that chemosensitivity testing of circulating tumor cells provides real-time information about the sensitivity of the tumor present in the patient, even at different times during therapy, and correlates with treatment success.展开更多
Since chemotherapy started in 1940s, chemosensitivity testing has been both a very attractive field and one fraught with potential pitfalls. Many methods were developed and brought initial promises, yet later ending i...Since chemotherapy started in 1940s, chemosensitivity testing has been both a very attractive field and one fraught with potential pitfalls. Many methods were developed and brought initial promises, yet later ending in disappointment and were eliminated. For example, in the 1970s clonogenic assay was generally believed to be the best testing method for predicting clinical outcome. However, technical problems including low evaluation rate limited its use. Currently, MTT, ATP, DISC and Kern’s assay hold better promises. Since the 90s, the study of molecular biology has been progressing rapidly. It accelerated the understanding of molecular mechanisms of drug response. Numerous papers were published, but only few techniques can be applied in clinical practice. This review summarizes the controversies and current progress of chemosensitivity assays based on available online information, and makes a suggestion about their future routine practice.展开更多
Objective:To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC),and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of...Objective:To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC),and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of adjuvant chemotherapy after NSCLC.Methods:Tumor tissues and adjacent non-tumor tissues of 92 patients with NSCLC who underwent surgery and adjuvant chemotherapy from January 2012 to June 2015 in the thoracic surgery department of our hospital were collected,methylation-specific PCR(MSP)was used to detect the methylation status of MGMT gene promoter in tissues,and the relationship between methylation of MGMT gene promoter and chemosensitivity,progression-free survival(PFS)and 3-year overall survival rate was analyzed.Results:The methylation rate of MGMT gene promoter in cancer tissue was 39.13%(36/92)higher than that in non-cancer tissue 3.26%(3/92)(P<0.05);methylation of MGMT gene promoter was associated with TNM stage,lymph node metastasis and tumor differentiation(P<0.05);the proportion of patients with recurrence,metastasis or death in methylation group was higher than that in non-methylation group(P<0.05);PFS and 3-year overall survival rate in methylated group were lower than those in non-methylated group(P<0.05);multivariate COX regression analysis showed that lymph node metastasis and promoter methylation of MGMT gene were independent risk factors for prognosis of NSCLC patients.Conclusion:MGMT gene promoter methylation is closely related to the chemosensitivity and prognosis of platinum-based adjuvant chemotherapy after NSCLC.It may be an important target to reverse the chemosensitivity of platinum-based chemotherapy and improve the prognosis of NSCLC.展开更多
Objective:To investigate the expressions of PKC , PKC and PKC in cervical cancer and their relationships with chemosensitivity.Methods: A total of 38 cases of patients with cervical cancer diagnosed in our hospital fr...Objective:To investigate the expressions of PKC , PKC and PKC in cervical cancer and their relationships with chemosensitivity.Methods: A total of 38 cases of patients with cervical cancer diagnosed in our hospital from November 2015 to November 2016 were selected, and the vascularization index (VI), flow index (FI) and vascular flow index (VFI) were measured by three-dimensional color Doppler ultrasound, then the expression levels of PKC , PKC and PKC mRNAs were detected by RT-PCR before and after chemotherapy. Western blot was used to detect the expression of PKC , PKC and PKC proteins in tissues, Spearman correlation analysis was performed to investigate the relationships between PKC , PKC and PKC mRNAs with chemosensitivity, Logisitic regression analysis was used to analyze the related factors affecting the sensitivity of chemotherapy.Results: After chemotherapy, the expression levels of PKC and PKC mRNAs and proteins were significantly decreased, the expressions of PKC mRNA and protein were significantly increased;the expression levels of PKC and PKC mRNAs and proteins in the effective group after chemotherapy were significantly lower than those before chemotherapy, the expressions of PKC mRNA and protein were significantly higher than those before chemotherapy;Spearman analysis showed that the expression levels of PKC and PKC mRNAs in cervical cancer tissues before chemotherapy were positively correlated with VI, FI and the percentage of residual tumor volume after chemotherapy, PKC was negatively correlated with VI, FI and residual tumor volume percentage after chemotherapy, and was not significantly correlated with VFI and tumor size before chemotherapy;Logistic regression analysis showed that PKC , PKC , PKC mRNAs, VI and FI were independent risk factors for chemosensitivity, lymph node metastasis and tumor volume were independent of chemosensitivity.Conclusion: PKC and PKC are highly expressed in cervical cancer tissues, and PKC is low expressed in cervical cancer tissues, they are closely related to chemosensitivity.展开更多
This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying mechanisms.In this study,we found t...This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying mechanisms.In this study,we found that the expression of lncRNA MEG3 was significantly lower in OS tissues and cell lines.Furthermore,lncRNA MEG3 overexpression enhanced chemosensitivity of OS by inhibiting cell proliferation,migration,autophagy,and promoting antitumor immunity.LncRNA MEG3 functioned as miR-21-5 sponge to regulate p53 expression in OS.Mechanically,lncRNA MEG3 promoted OS chemosensitivity by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy.Collectively,this study provided the evidence that lncRNA MEG3 might be a promising therapeutic target for OS chemoresistance.展开更多
To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,inva...To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,invasion,autophagy,and temozolomide(TMZ)sensitivity in the U251 cell line using in vitro and in vivo experiments.Cell viability was tested by a cell counting kit-8(CCK8)kit;migration and invasion were checked by the scratching assay;apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining and flow cytometry.The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506.Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment.We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ,which was mediated by autophagy.FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation.MiR-506 could downregulate E26 transformation-specific 1(ETS1)expression by targeting its 3'-untranslated region(UTR).Interestingly,ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells.Consistently,both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models.Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity.Thus,the above axis might be a promising therapeutic target for GBM.展开更多
MiR-142-3p has been reported to act as a tumor suppressor in breast cancer.However,the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown.Here,we foun...MiR-142-3p has been reported to act as a tumor suppressor in breast cancer.However,the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown.Here,we found that miR-142-3p was significantly downregulated in the doxorubicin(DOX)-resistant MCF-7 cell line(MCF-7/DOX).MiR-142-3p overexpression increased DOX sensitivity and enhanced DOXinduced apoptosis in breast cancer cells.High-mobility group box 1(HMGB1)is a direct functional target of miR-142-3p in breast cancer cells and miR-142-3p negatively regulated HMGB1 expression.Moreover,overexpres sion of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by miR-142-3p up-regulation.In conclusion,miR-142-3p overexpression may inhibit autophagy and promote the drug sensitivity of breast cancer cells to DOX by targeting HMGB 1.The miR-142-3 p/HMGB1 axis might be a novel target to regulate the drug resistance of breast cancer patients.展开更多
Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma(OSCC)treatment,it exerts multiple side effects and poor chemosensitivity.Nitrate reportedly demonstrates several ...Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma(OSCC)treatment,it exerts multiple side effects and poor chemosensitivity.Nitrate reportedly demonstrates several beneficial biological functions,and synthesized nitrates enhance the therapeutic efficacy of chemotherapy.However,the role of inorganic nitrate in cisplatin chemotherapy remains unclear.We therefore investigated the effect of inorganic nitrate exerted on cisplatin sensitivity in OSCC.We found that nitrate did not affect OSCC cell growth and apoptosis in OSCC cells and OSCC xenograft tumor animal studies.Cisplatin induced REDD1 expression and AKT activation in OSCC.However,nitrate could increase cisplatin chemosensitivity,reduce its REDD1 expression,and attenuate AKT signaling activation in OSCC cells.Dysregulation of high levels of REDD1,which could enhance AKT activation,was positively associated with poor prognosis in OSCC patients.Thus,reduced REDD1 expression and retarded AKT activation induced by inorganic nitrate might be a new potential approach to the sensitization of oral cancer to cisplatin treatment in the future.展开更多
Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelop...Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment,the paired box 5(PAX5)gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma(ESCC)pathogenesis remains unclear.Methods:To elucidate the role of PAX5 in ESCC,eight ESCC cell lines,51 primary ESCC tissue samples,and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas(TCGA)was queried.PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting.Cell apoptosis,proliferation,and chemosensitivity were detected by flow cytometry,colony formation assays,and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing.Tumor xenograft models were established for in vivo verification.Results:PAX5 methylation was found in 37.3%(19/51)of primary ESCC samples,which was significantly associated with age(P=0.007)and tumor-node-metastasis stage(P=0.014).TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation(r=-0.189,P=0.011 for cg00464519 and r=-0.228,P=0.002 for cg02538199).Restoration of PAX5 expression suppressed cell proliferation,promoted apoptosis,and inhibited tumor growth of ESCC cell lines,which was verified in xenografted mice.Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels.A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays.Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel.Silencing of PAX5 induced resistance of KYSE450 cells to these drugs.Conclusions:As a tumor suppressor gene regulated by promoter region methylation in human ESCC,PAX5 inhibits proliferation,promotes apoptosis,and induces activation of p53 signaling.PAX5 may serve as a chemosensitive marker of ESCC.展开更多
Introduction:Multiple myeloma(MM)is a geriatric dis-ease with onset at an average age of approximately 61years.With the aging of the population,the incidence rate ofMM is climbing.In the United States,the annual incid...Introduction:Multiple myeloma(MM)is a geriatric dis-ease with onset at an average age of approximately 61years.With the aging of the population,the incidence rate ofMM is climbing.In the United States,the annual incidence展开更多
基金Supported by National Natural Science Foundation of China,No.81272480/H1609
文摘AIM: To investigate the effect of Girdin knockdown on the chemosensitivity of colorectal cancer cells to oxaliplatin and the possible mechanisms involved.METHODS: Four siRNAs targeting Girdin were transfected into the chemoresistant colorectal cancer cell line DLD1. Real-time polymerase chain reaction(PCR) was employed to assess Girdin mRNA expression and the most effective siRNA was chosen for conversion into shRNA. Then, DLD1 cells were infected with lentiviruses expressing the Girdin shRNA and a scramble control, respectively, and Girdin mRNA and protein expression levels were assessed by real-time PCR and Western blotting. Furthermore, microarray experiments were used to assess global gene expression profile after Girdin suppression in DLD1 cells. Finally, the cytotoxic effect of simultaneous treatment with oxaliplatin and adriamycin(an inhibitor of a significantly downregulated gene after Girdin suppression in DLD1 cells) was examined by MTT assay.RESULTS: The most effective siRNA suppressed Girdinexpression with an inhibition efficiency of 57%. Compared with the scramble control, DLD1 cells infected with the Girdin shRNA displayed decreased Girdin mRNA and protein levels(P < 0.05), and Girdin knockdown significantly enhanced chemosensitivity to oxaliplatin in colorectal cancer cells(P < 0.05). Microarray data revealed that 381 and 162 genes were upregulated and downregulated in response to Girdin reduction, respectively, with ratios > 1.2 or < 0.8(P < 0.01). Interestingly, TOP2B(DNA topoisomerase 2-β) was downregulated(ratio = 0.78, P = 0.0001) and oxaliplatin/adriamycin combination resulted in increased cell death compared with treatments with individual agents(P < 0.05).CONCLUSION: Girdin knockdown enhances chemosensitivity of colorectal cancer cells to oxaliplatin via TOP2B down-regulation. These findings provide a promising approach to overcome the chemoresistance of colorectal cancer cells.
文摘Oligodendroglial tumors frequently have deletions ofchromosomal loci on lp and l9q.Loas of heterozygosity(LOH)of chromosome 10 may be a negative prognostic factor.We reviewed 23 patients with oligodendroglial tumors,toevaluate the frequency of lp and 10q LOH and correlate with clinical outcome.Three loci(DlS402,DlSl 172,MCT118)on lp and 2 loci(Dl0S520 and D10S521)on 10q were analyzed for LOH using PCR techniques.
基金supported by Science and Technology research Project of Zhengzhou City(121PPTGG499-2)
文摘Objective:To study the influence of curcumin on chemosensitivity of nephroblastoma cells.Methods:Human nephroblastoma cells line SK-NEP-1 was transplanted to the nude mice subcutaneously to establish the implantation tumor model of human nephroblastoma cells.A total of 30 tumor-bearing mice were divided into three groups of ten randomly.The routine chemotherapy group was given vincristine(0.05 mg/mL·0.2 mL/d) and actinomycin D(15 ng/mL·0.2 mL/d) combined chemotherapy regime.The curcumin chemotherapy group was given the same combined chemotherapy regimens and curcumin(30 mg/kg/d) by intraperitoneal injection.The control group was given normal saline(NS) of the same volume by intraperitoneal injection.Continuous administration would be kept for 4 weeks and 3 days a week.The volumetric changes of every group were recorded.The serum of every group in different time was collected and the VEGF content was detected by ELISA.All mice were cercrificed and the tumor tissues were stripped and weighed after 4 weeks’ treatment.The tumor inhibition rate was calculated.The cell proliferation activity and apoptosis rate were detected by MTT and flow cytometry method.All data were statistically analyzed by SPSS 19.0.Results:The tumor volume,serum VEGF content,tumor inhibition rate,cell proliferation activity and apoptosis rate of routine chemotherapy group and curcumin chemotherapy group had significant differences comparing with the control group(P<0.05) after 4-week’s treatment.The cancer growth of curcumin chemotherapy group was obviously decreased and even tended to shrink comparing with routine chemotherapy group(χ2=15.732,P=0.007).The cell proliferation activity was significantly reduced and the apoptosis rate was significantly higher,(χ~2=9.427,P=0.012)which showing the effect of chemotherapy was enhanced.Conclusions:The chemosensitivity of nephroblastoma cells could be improved by curcumin,then the effect of preoperative adjuvant chemotherapy scheme would be enhanced,the growth of nephroblastoma cells would be inhibited and the surgical risk of nephroblastoma would be reduced.
基金the National Natural Science Foundation of China! (No. 39700143).
文摘Objective: To determine the effects on the cell growth, tumorigenicity and chemosensitivity of p16/CDK4I in human glioma. Methods: p16 gene was transfected into U251 cells by lipofectin. Expression of exogenous p16 gene was confirmed by immunohistochemistry and Northern blot. The effects of exogenous p16 gene on the growth and chemosensitivity to teniposide were examined. Results: Expression of exogenous p16 gene inhibited the growth dramatically in vitro. G1 arrest of tumor cells was observed. However, wt p16-positive U251 was less sensitive than control cell lines and the number of apoptotic cells after chemotherapy was reduced. Conclusion: The expression of exogenous p16 gene could inhibit the growth of glioma. On the other hand, the chemosensitivity to teniposide of p16-positive U251 was decreased.
基金This work was supported by the National Research Program of China(2017YFA0505803 and 2017YFC0908100)the State Key Project for Infectious Diseases(2018ZX10732202-001)+2 种基金National Natural Science Foundation of China(81790633,81672860,61922047,81422032,and 81902412)National Natural Science Foundation of Shanghai,China(17ZR143800)National Science Foundation for Distinguished Young Scholars of China(81702298).
文摘Intrahepatic cholangiocarcinoma(ICC)is the second most common liver cancer.Chemotherapy remains the main therapeutic strategy for advanced ICC patients,but chemosensitivity varies individually.Here,we applied cytometry by time-of-flight(CyTOF)to establish the immune profile of peripheral blood mononuclear cells(PBMCs)on the single-cell level at indicated time points before,during,and after chemotherapy.Multiplex immunofluorescence staining was applied to examine the spatial distribution of certain immune clusters.Tissue microarrays(TMAs)were used for prognostic evaluation.A total of 20 ICC patients treated with gemcitabine(GEM)were enrolled in our study,including eight cases with good response(R)and 12 cases with non-response(NR).Tremendous changes in PBMC composition,including an increased level of CD4/CD8 double-positive T cells(DPT),were observed after chemotherapy.Patients with higher level of CD4^(+)CD45RO^(+)CXCR3^(+)T cells before treatment had a favorable response to chemotherapy.Our study identified a positive correlation between the percentage of T cell subpopulations and clinical response after chemotherapy,which suggests that it is practical to predict the potential response before treatment by evaluating the proportions of the cell population in PBMCs.
基金Supported by a grant from the Capital’s Funds for Health Improvement and Research(No.Z131107002213013)
文摘Objective The aim of the study was to evaluate the role of ATP-based tumor chemosensitivity assay(ATP-TCA) in patients with platinum-resistant recurrent ovarian cancer(PRROC).Methods A total of 43 patients with PRROC who underwent chemotherapy based on the results of ATPTCA in the Cancer Hospital,Chinese Academy of Medical Sciences were included in the present study.As controls,we selected another 43 patients with PRROC who were treated at the physician's discretion within the same time period and had the same clinical characteristics as the patients in the ATP-TCA group.Logrank test and Cox proportional hazards model were adopted for analysis.Results A total of 86 patients were retrospectively analyzed in the present study.Patients were routinely monitored to evaluate the rate of progression-free survival(PFS).The median follow-up time was 13 months.The PFS for the ATP-TCA and control groups was 5 and 3 months,respectively(P = 0.027).Multivariate analysis showed that the type of treatment was an independent prognostic factor for PFS(P = 0.040;HR:0.623;95% CI:0.313–0.973).Subgroup analysis showed that among patients with a treatmentfree interval(TFI) of ≥ 3 months(n = 50),those in the ATP-TCA group had longer PFS than those in the control group(7 vs 4 months,P = 0.010).Meanwhile,the median PFS of patients who underwent ≤ 2 prior chemotherapy regimens(PCR,n = 52) in the ATP-TCA and control groups was 6 months and 4 months,respectively(P = 0.025).Conclusion ATP-TCA-directed chemotherapy might improve the PFS in PRROC.In particular,the survival benefit from ATP-TCA is higher in patients with a TFI of ≥ 3 months or treated with ≤ 2 PCR.
文摘Objective The aim of the study was to investigate whether colon cancer stem cells induced by epidermal growth factor(EGF) to enter the cell cycle enhanced the chemosensitivity of colon cancer.Methods In vitro,EGF was used to stimulate the entry of human colon cancer HCT116 cells into the cell cycle.Before and after treatment with EGF,CD133+ HCT116 cells were collected and flow cytometry was conducted to determine the apoptosis rate based on the 5-Fu and Ki-67 expression rates.The cell cycle distribution of the two groups was also determined.In vivo,a subcutaneous xenograft model of HCT116 human colon cancer cell lines in nude mice was established.The nude mice were divided into two groups and treated with EGF and 5-Fu,respectively.Differences in the growth of implanted tumors revealed the efficiency of cycle-induction combined chemotherapy.Results(1) After EGF stimulation,the S-G2/M proportion of CD133+ HCT116 cells and Ki67 expression were increased,indicating that more cancer stem cells entered the cell cycle and promoted proliferation;(2) After EGF stimulation,CD133+ HCT116 cells showed a higher apoptosis rate induced by 5-Fu.(3) Animal experiments showed that the group subjected to combined treatment with EGF and 5-Fu had smaller tumor sizes compared to the group treated with 5-Fu alone.Conclusion EGF enhanced tumor sensitivity to chemotherapeutic drugs,likely by promoting tumor stem cells to enter the cell cycle.
文摘Finding effective cancer treatment is a challenge, because the sensitivity of the cancer stems from both intrinsic cellular properties and acquired resistances from prior treatment. Previous research has revealed individual protein markers that are significant to chemosensitivity prediction. Our goal is to find correlated protein markers which are collectively significant to chemosensitivity prediction to complement the individual markers already reported. In order to do this, we used the D’ correlation measurement to study the feature selection correlations for chemosensitivity prediction of 118 anticancer agents with putatively known mechanisms of action. Three data-sets on the NCI-60 were utilized in this study: two protein datasets, one previously studied for chemosensitivity prediction and another novel to this topic, and one DNA copy number dataset. To validate our approach, we identified the protein markers that were strongly correlated by our analysis with the individual protein markers found in previous studies. Our feature analysis discovered highly correlated protein marker pairs, based on which we found individual protein markers with medical significance. While some of the markers uncovered were consistent with those previously reported, others were original to this work. Using these marker pairs we were able to further correlate the cellular functions associated with them. As an exploratory analysis, we discovered feature selection correlation patterns between and within different drug mechanisms of action for each of our datasets. In conclusion, the highly correlated protein marker pairs as well as their functions found by our feature analysis are validated by previous studies, and are shown to be medically significant, demonstrating D’ as an effective measurement of correlation in the context of feature selection for the first time.
文摘Several gene signatures have been identified to build predictors of chemosensitivity for breast cancer. It is crucial to understand how each gene in a signature contributes to the prediction, i.e., to make the prediction model interpretable instead of using it as a black box. We utilized Random Forests (RFs) to build two interpretable predictors of pathologic complete response (pCR) based on two gene signatures. One signature consisted of the top 31 probe sets (27 genes) differentially expressed between pCR and residual disease (RD) chosen from a previous study, and the other consisted of the genes involved in Notch singling pathway (113 genes). Both predictors had a higher accuracy (82% v 76% & 79% v 76%), a higher specificity (91% v 71% & 98% v 71%), and a higher positive predictive value (PPV) (68% v 52% & 73% v 52%)) than the predictor in the previous study. Furthermore, Random Forests were employed to calculate the importance of each gene in the two signatures. Findings of our functional annotation suggested that the important genes identified by the feature selection scheme of Random Forests are of biological significance.
文摘Various gene signatures of chemosensitivity in breast cancer have been discovered. One previous study employed t-test to find a signature of 31 probe sets (27 genes) from a group of patients who received weekly preoperative chemotherapy. Based on this signature, a 30-probe set diagonal linear discriminant analysis (DLDA-30) classifier of pathologic complete response (pCR) was constructed. In this study, we sought to uncover a signature that is much smaller than the 31 probe sets and yet has enhanced predictive performance. A signature of this nature could inform us what genes are essential in response prediction. Genetic algorithms (GAs) and sparse logistic regression (SLR) were employed to identify two such small signatures. The first had 13 probe sets (10 genes) selected from the 31 probe sets and was used to build a SLR predictor of pCR (SLR-13), and the second had 14 probe sets (14 genes) selected from the genes involved in Notch signaling pathway and was used to develop another SLR predictor of pCR (SLR-Notch-14). The SLR-13 and SLR-Notch-14 had a higher accuracy and a higher positive predictive value than the DLDA-30 with much lower P values, suggesting that our two signatures had their own discriminative power with high statistical significance. The SLR prediction model also suggested the dual role of gene RNUX1 in promoting residual disease (RD) or pCR in breast cancer. Our results demonstrated that the multivariable techniques such as GAs and SLR are effective in finding significant genes in chemosensitivity prediction. They have the advantage of revealing the interacting genes, which might be missed by single variable techniques such as t-test.
文摘Background: Chemotherapy is a mainstay of tumor therapy, however, it is predominantly applied according to empirically developed recommendations derived from statistical relapse rates occurring years after the treatment in the adjuvant situation and from progression-free interval data in the metastatic situation, without any possibility of individually determining the efficacy in the adjuvant situation and with loss of time and quality of life in the metastatic situation if the drugs chosen are not effective. Here, we present a method to determine the efficiency of chemotherapeutic drugs using tumor cells circulating in blood as the part of the tumor actually available in the patient’s body for chemosensitivity testing. Methodology/Principal Findings: After only red blood cell lysis, omitting any enrichment (analogous to other blood cell enumeration methods, including rare CD34 cells), the white cells comprising the circulating epithelial tumor cells (CETC) are exposed to the drugs in question in different concentrations and for different periods of time. Staining with a fluorescence-labeled anti-epithelial antibody detects both vital and dying tumor cells, distinguishing vital from dying cells through membrane permeability and nuclear staining with propidium iodide. Increasing percentages of dying tumor cells are observed dependent on time and concentration. The sensitivity can vary during therapy and was correlated with decrease or increase in CETC and clinical outcome. Conclusions/Significance: Thus, we are able to show that chemosensitivity testing of circulating tumor cells provides real-time information about the sensitivity of the tumor present in the patient, even at different times during therapy, and correlates with treatment success.
文摘Since chemotherapy started in 1940s, chemosensitivity testing has been both a very attractive field and one fraught with potential pitfalls. Many methods were developed and brought initial promises, yet later ending in disappointment and were eliminated. For example, in the 1970s clonogenic assay was generally believed to be the best testing method for predicting clinical outcome. However, technical problems including low evaluation rate limited its use. Currently, MTT, ATP, DISC and Kern’s assay hold better promises. Since the 90s, the study of molecular biology has been progressing rapidly. It accelerated the understanding of molecular mechanisms of drug response. Numerous papers were published, but only few techniques can be applied in clinical practice. This review summarizes the controversies and current progress of chemosensitivity assays based on available online information, and makes a suggestion about their future routine practice.
基金Research Project of Traditional Chinese Medicine of Shaanxi Traditional Chinese Medicine Administration in 2017.Project No:LCMS052.
文摘Objective:To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC),and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of adjuvant chemotherapy after NSCLC.Methods:Tumor tissues and adjacent non-tumor tissues of 92 patients with NSCLC who underwent surgery and adjuvant chemotherapy from January 2012 to June 2015 in the thoracic surgery department of our hospital were collected,methylation-specific PCR(MSP)was used to detect the methylation status of MGMT gene promoter in tissues,and the relationship between methylation of MGMT gene promoter and chemosensitivity,progression-free survival(PFS)and 3-year overall survival rate was analyzed.Results:The methylation rate of MGMT gene promoter in cancer tissue was 39.13%(36/92)higher than that in non-cancer tissue 3.26%(3/92)(P<0.05);methylation of MGMT gene promoter was associated with TNM stage,lymph node metastasis and tumor differentiation(P<0.05);the proportion of patients with recurrence,metastasis or death in methylation group was higher than that in non-methylation group(P<0.05);PFS and 3-year overall survival rate in methylated group were lower than those in non-methylated group(P<0.05);multivariate COX regression analysis showed that lymph node metastasis and promoter methylation of MGMT gene were independent risk factors for prognosis of NSCLC patients.Conclusion:MGMT gene promoter methylation is closely related to the chemosensitivity and prognosis of platinum-based adjuvant chemotherapy after NSCLC.It may be an important target to reverse the chemosensitivity of platinum-based chemotherapy and improve the prognosis of NSCLC.
文摘Objective:To investigate the expressions of PKC , PKC and PKC in cervical cancer and their relationships with chemosensitivity.Methods: A total of 38 cases of patients with cervical cancer diagnosed in our hospital from November 2015 to November 2016 were selected, and the vascularization index (VI), flow index (FI) and vascular flow index (VFI) were measured by three-dimensional color Doppler ultrasound, then the expression levels of PKC , PKC and PKC mRNAs were detected by RT-PCR before and after chemotherapy. Western blot was used to detect the expression of PKC , PKC and PKC proteins in tissues, Spearman correlation analysis was performed to investigate the relationships between PKC , PKC and PKC mRNAs with chemosensitivity, Logisitic regression analysis was used to analyze the related factors affecting the sensitivity of chemotherapy.Results: After chemotherapy, the expression levels of PKC and PKC mRNAs and proteins were significantly decreased, the expressions of PKC mRNA and protein were significantly increased;the expression levels of PKC and PKC mRNAs and proteins in the effective group after chemotherapy were significantly lower than those before chemotherapy, the expressions of PKC mRNA and protein were significantly higher than those before chemotherapy;Spearman analysis showed that the expression levels of PKC and PKC mRNAs in cervical cancer tissues before chemotherapy were positively correlated with VI, FI and the percentage of residual tumor volume after chemotherapy, PKC was negatively correlated with VI, FI and residual tumor volume percentage after chemotherapy, and was not significantly correlated with VFI and tumor size before chemotherapy;Logistic regression analysis showed that PKC , PKC , PKC mRNAs, VI and FI were independent risk factors for chemosensitivity, lymph node metastasis and tumor volume were independent of chemosensitivity.Conclusion: PKC and PKC are highly expressed in cervical cancer tissues, and PKC is low expressed in cervical cancer tissues, they are closely related to chemosensitivity.
基金supported by The National Natural Science Foundation of China(No.82072979).
文摘This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying mechanisms.In this study,we found that the expression of lncRNA MEG3 was significantly lower in OS tissues and cell lines.Furthermore,lncRNA MEG3 overexpression enhanced chemosensitivity of OS by inhibiting cell proliferation,migration,autophagy,and promoting antitumor immunity.LncRNA MEG3 functioned as miR-21-5 sponge to regulate p53 expression in OS.Mechanically,lncRNA MEG3 promoted OS chemosensitivity by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy.Collectively,this study provided the evidence that lncRNA MEG3 might be a promising therapeutic target for OS chemoresistance.
基金supported by the National Natural Science Foundation of China(Nos.81402076,81872072,and 82073274)the Science Technology Commission of Shanghai Municipality(No.20S11900700)。
文摘To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,invasion,autophagy,and temozolomide(TMZ)sensitivity in the U251 cell line using in vitro and in vivo experiments.Cell viability was tested by a cell counting kit-8(CCK8)kit;migration and invasion were checked by the scratching assay;apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining and flow cytometry.The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506.Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment.We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ,which was mediated by autophagy.FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation.MiR-506 could downregulate E26 transformation-specific 1(ETS1)expression by targeting its 3'-untranslated region(UTR).Interestingly,ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells.Consistently,both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models.Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity.Thus,the above axis might be a promising therapeutic target for GBM.
基金the financial support by National Natural Science Foundation of China(Nos.81330007 and U1601227)the Science and Technology Programs of Guangdong Province(Nos.2014A050503047 and 2015B020225006,China)National Natural Science Foundation of China(81700382)
文摘MiR-142-3p has been reported to act as a tumor suppressor in breast cancer.However,the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown.Here,we found that miR-142-3p was significantly downregulated in the doxorubicin(DOX)-resistant MCF-7 cell line(MCF-7/DOX).MiR-142-3p overexpression increased DOX sensitivity and enhanced DOXinduced apoptosis in breast cancer cells.High-mobility group box 1(HMGB1)is a direct functional target of miR-142-3p in breast cancer cells and miR-142-3p negatively regulated HMGB1 expression.Moreover,overexpres sion of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by miR-142-3p up-regulation.In conclusion,miR-142-3p overexpression may inhibit autophagy and promote the drug sensitivity of breast cancer cells to DOX by targeting HMGB 1.The miR-142-3 p/HMGB1 axis might be a novel target to regulate the drug resistance of breast cancer patients.
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-031)Beijing Hospitals Authority of Hospitals’Mission Plan(SML20151401,Capital Medical University)+1 种基金Beijing Municipality Government grants(Beijing Scholar Program—PXM2020_014226_000005,PXM2019_014226_000039,PXM2019_014226_000011,PXM2018_014226_000021,PXM2017_014226_000023,PXM2018_193312_000006_0028S643_FCG,PXM2016_014226_000034)the National Natural Science Foundation of China(91649124).
文摘Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma(OSCC)treatment,it exerts multiple side effects and poor chemosensitivity.Nitrate reportedly demonstrates several beneficial biological functions,and synthesized nitrates enhance the therapeutic efficacy of chemotherapy.However,the role of inorganic nitrate in cisplatin chemotherapy remains unclear.We therefore investigated the effect of inorganic nitrate exerted on cisplatin sensitivity in OSCC.We found that nitrate did not affect OSCC cell growth and apoptosis in OSCC cells and OSCC xenograft tumor animal studies.Cisplatin induced REDD1 expression and AKT activation in OSCC.However,nitrate could increase cisplatin chemosensitivity,reduce its REDD1 expression,and attenuate AKT signaling activation in OSCC cells.Dysregulation of high levels of REDD1,which could enhance AKT activation,was positively associated with poor prognosis in OSCC patients.Thus,reduced REDD1 expression and retarded AKT activation induced by inorganic nitrate might be a new potential approach to the sensitization of oral cancer to cisplatin treatment in the future.
基金National Science Foundation of China(NSFC Nos.31671298,81802390,and 81672462)Natural Science Foundation of Beijing(No.7202187)+3 种基金National Key Research and Development Program of China(Nos.2016YFC0905200,2016YFC0905302,and 2017YFC 1308900)National Geriatrics Center Funding(No.NCRCG-PLAGH-2018002)Key Projects of Clinical Application and Promotion with Capital Characteristics(No.Z161100000516003)Military Medical Special Program for Youth of Chinese People's Liberation Army General Hospital(No.QNF19037)。
文摘Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment,the paired box 5(PAX5)gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma(ESCC)pathogenesis remains unclear.Methods:To elucidate the role of PAX5 in ESCC,eight ESCC cell lines,51 primary ESCC tissue samples,and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas(TCGA)was queried.PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting.Cell apoptosis,proliferation,and chemosensitivity were detected by flow cytometry,colony formation assays,and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing.Tumor xenograft models were established for in vivo verification.Results:PAX5 methylation was found in 37.3%(19/51)of primary ESCC samples,which was significantly associated with age(P=0.007)and tumor-node-metastasis stage(P=0.014).TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation(r=-0.189,P=0.011 for cg00464519 and r=-0.228,P=0.002 for cg02538199).Restoration of PAX5 expression suppressed cell proliferation,promoted apoptosis,and inhibited tumor growth of ESCC cell lines,which was verified in xenografted mice.Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels.A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays.Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel.Silencing of PAX5 induced resistance of KYSE450 cells to these drugs.Conclusions:As a tumor suppressor gene regulated by promoter region methylation in human ESCC,PAX5 inhibits proliferation,promotes apoptosis,and induces activation of p53 signaling.PAX5 may serve as a chemosensitive marker of ESCC.
文摘Introduction:Multiple myeloma(MM)is a geriatric dis-ease with onset at an average age of approximately 61years.With the aging of the population,the incidence rate ofMM is climbing.In the United States,the annual incidence
