目的探讨声带癌前病变组织中基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinases 1,TIMP-1)、果蝇母亲DDP同源物4(drosophila mothers against DDP homolog 4,Smad4)表达水平与术后复发和恶变的相关性。方法回顾性分析2018...目的探讨声带癌前病变组织中基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinases 1,TIMP-1)、果蝇母亲DDP同源物4(drosophila mothers against DDP homolog 4,Smad4)表达水平与术后复发和恶变的相关性。方法回顾性分析2018年8月~2021年8月郑州大学第一附属医院收治的162例声带癌前病变患者的临床和病理资料,收集手术切除癌前病变组织(癌前病变组)及病变旁正常黏膜组织(对照组),采用免疫组织化学法检测组织中TIMP-1、Smad4表达情况。分析TIMP-1、Smad4阳性率与临床病理特征的关系,并采用Kaplan-Meier法和Cox回归分析法分析其对术后复发和恶变的影响。结果与对照组正常黏膜组织比较,癌前病变组的TIMP-1阳性率较高,Smad4阳性率较低(P<0.05)。不同病变范围、是否累及前连合、不同程度上皮异常增生患者的TIMP-1、Smad4阳性率存在差异(P<0.05)。术后随访时间24~60个月,中位随访时间36个月,随访期间失访患者6例,随访率96.30%(156/162),随访期间术后复发35例(21.60%),术后恶变16例(9.88%);Kaplan-Meier生存分析显示,TIMP-1阳性患者术后复发率和恶变率高于TIMP-1阴性患者(P<0.05);Smad4阴性患者术后复发率和恶变率高于Smad4阳性患者(P<0.05)。多因素Cox回归分析显示,喉咽反流、病变范围>1/2、中/重度异型增生、TIMP-1阳性、Smad4阴性是复发的独立危险因素(P<0.05),年龄>60岁、累及前连合、TIMP-1阳性、Smad4阴性是恶变的独立危险因素(P<0.05)。结论声带癌前病变组织中TIMP-1高表达、Smad4低表达,且TIMP-1阳性、Smad4阴性表达者术后复发和恶变风险较高。展开更多
Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS ...Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR,and mir-3168 mimic,inhibitor and negative control were synthesized.They were transfected into AGS and AGS/DDP gastric cancer cells,respectively.The expression of mir-3168 and TP53 mRNA was detected by qPCR.Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment,apoptosis was detected by flow cytometry,cell invasion was detected by Transwell,and TP53 protein expression was detected by western blot,The database predicted the binding sites of mir-3168 and TP53.According to the binding sites,the double luciferase experiment was used to verify the binding of mir-3168 and TP53.Results:Compared with cisplatin sensitive gastric cancer cell AGS,mir-3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP;mir-3168 mimic promotes cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 inhibitor inhibits cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and promotes apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 mimic inhibits the expression of TP53 mRNA and protein,and mir-3168 inhibitor promotes the expression of TP53 mRNA and protein;Targetscan database predicted that there was a binding point between mir-3168 and TP53,and the double luciferase experiment suggested that mir-3168 was bound to TP53 through the predicted binding site.Conclusion:mir-3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.展开更多
Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the...Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.展开更多
The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the c...The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.展开更多
The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ...The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.展开更多
Translesion DNA synthesis(TLS)can bypass DNA lesions caused by chemotherapeutic drugs,which usually result in drug resistance.Given its key role in mutagenesis and cell survival after DNA damage,inhibition of the TLS ...Translesion DNA synthesis(TLS)can bypass DNA lesions caused by chemotherapeutic drugs,which usually result in drug resistance.Given its key role in mutagenesis and cell survival after DNA damage,inhibition of the TLS pathway has emerged as a potential target for improving the efficacy of DNA-damaging agents such as cisplatin(CDDP),a widely used anticancer agent.Unfortunately,few suitable natural TLS inhibitors have been reported.Here,we found that a triterpenoid compound Ganoboninketal C(26-3)from Ganoderma boninense,a traditional Chinese medicine,can impair CDDP-induced TLS polymerase eta(Polη)focus formation,PCNA monoubiquitination as well as mutagenesis.Moreover,26-3 can significantly sensitize tumor cells to CDDP killing and reduce the proportion of cancer stem cells in AGS and promote apoptosis after CDDP exposure.Interestingly,26-3 can also sensitize tumor cells to Gefitinib therapy.Mechanistically,through RNA-seq analysis,we found that 26-3 could abrogate the CDDP-induced upregulation of Polηand PIDD(p53-induced protein with a death domain),2 known factors promoting TLS pathway.Furthermore,we found that activating transcription factor 3 is a potential novel TLS modulator.Taken together,we have identified a natural TLS inhibitor 26-3,which can be potentially used as an adjuvant to improve clinical efficacy.展开更多
Celecoxib,a cyclooxygenase-2 inhibitor,can enhance the efficacy of chemotherapy;however,its effect seems inconsistent.In this study,we investigated whether celecoxib would increase the antiproliferative effects of cis...Celecoxib,a cyclooxygenase-2 inhibitor,can enhance the efficacy of chemotherapy;however,its effect seems inconsistent.In this study,we investigated whether celecoxib would increase the antiproliferative effects of cisplatin in human lung cancer cells.Our data demonstrated the synergistic effects of celecoxib with cisplatin in wild-type p53 cells and their antagonistic effects inmutated or deleted p53 cells.Combination indices of 0.82 to 0.93 reflected a synergistic effect between celecoxib and cisplatin in lung cancer cells with wild-type p53.Combination indices of 1.63 to 3.00 reflected antagonism between celecoxib and cisplatin in lung cancer cells with mutated or deleted p53.Compared with that in cells with mutated or deleted p53,apoptosis significantly increased with the addition of celecoxib and cisplatin in wild-type p53 cells(P<0.05).Moreover,the results in vivo were similar to those in vitro:celecoxib combinedwith cisplatin slowed tumor growth in wild-type p53 groups and not in mutated or deleted p53 groups.In addition,celecoxib promoted p53 translocation into the nucleus and upregulated active p53 expression in wild-type p53 cells.Celecoxib combined with cisplatin upregulated PUMA(PUMA is a downstream gene of p53)after active p53 increased in wild-type p53 cells.In summary,the combination of celecoxib and cisplatin demonstrates clear synergistic effects in wild-type p53 cells and antagonistic effects inmutated or deleted p53 cells.The synergistic effect was achieved by apoptosis,induced by upregulating PUMA.Our results will provide a new treatment strategy for patients carrying wild-type p53,insensitive to cisplatin.展开更多
Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent...Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent,cisplatin,is diminished in patients with poor prognoses.Methods:Various bioinformatics databases were utilized to examine Carboxylesterase 1(CES1)gene expression,clinicopathologic features,patient survival analysis,and gene function.An organoid model of HNSCC was established,along with the induction of drug-resistant HNSCC in the organoid model.CES1 expression was assessed using qRT-PCR and Western Blot,and differential markers were identified through transcriptome sequencing.Knockdown and overexpression models of CES1 were created in SCC-9 and patient-derived organoid(PDO)cells using shRNA and lentivirus to investigate the tumor biology and cisplatin resistance associated with CES1.Results:Research in bioinformatics has uncovered a strong correlation between the expression level of CES1 and the prognosis of HNSCC.The data suggests a significant link between CES1 expression and tobacco smoking.RNA-sequencing revealed a notable increase in CES1 expression in HNSCC-PDOcis-R cells compared to the parental PDO cells.Subsequently,we performed in vitro studies by HNSCC-PDO and SCC-9 and found that CES1-overexpressing cells exhibited reduced sensitivity to cisplatin and stronger tumor malignant biological behavior compared with CES1-knockdown cells.Conclusion:The observed association between CES1 expression and tobacco smoking implies a potential influence of smoking on the efficacy of cisplatin-based chemotherapy in HNSCC through the regulation of CES1 expression.展开更多
文摘目的探讨声带癌前病变组织中基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinases 1,TIMP-1)、果蝇母亲DDP同源物4(drosophila mothers against DDP homolog 4,Smad4)表达水平与术后复发和恶变的相关性。方法回顾性分析2018年8月~2021年8月郑州大学第一附属医院收治的162例声带癌前病变患者的临床和病理资料,收集手术切除癌前病变组织(癌前病变组)及病变旁正常黏膜组织(对照组),采用免疫组织化学法检测组织中TIMP-1、Smad4表达情况。分析TIMP-1、Smad4阳性率与临床病理特征的关系,并采用Kaplan-Meier法和Cox回归分析法分析其对术后复发和恶变的影响。结果与对照组正常黏膜组织比较,癌前病变组的TIMP-1阳性率较高,Smad4阳性率较低(P<0.05)。不同病变范围、是否累及前连合、不同程度上皮异常增生患者的TIMP-1、Smad4阳性率存在差异(P<0.05)。术后随访时间24~60个月,中位随访时间36个月,随访期间失访患者6例,随访率96.30%(156/162),随访期间术后复发35例(21.60%),术后恶变16例(9.88%);Kaplan-Meier生存分析显示,TIMP-1阳性患者术后复发率和恶变率高于TIMP-1阴性患者(P<0.05);Smad4阴性患者术后复发率和恶变率高于Smad4阳性患者(P<0.05)。多因素Cox回归分析显示,喉咽反流、病变范围>1/2、中/重度异型增生、TIMP-1阳性、Smad4阴性是复发的独立危险因素(P<0.05),年龄>60岁、累及前连合、TIMP-1阳性、Smad4阴性是恶变的独立危险因素(P<0.05)。结论声带癌前病变组织中TIMP-1高表达、Smad4低表达,且TIMP-1阳性、Smad4阴性表达者术后复发和恶变风险较高。
基金This study was supported by National Natural Science Foundation of China(81960303)Youjiang Medical College for Nationalities Affiliated Hospital(R202011710)+6 种基金Youjiang Medical College for Nationalities Affiliated Hospital,Youjiang Key Talents Research Project(Y20212603)Guangxi Key Laboratory of Molecular Pathology of Hepatobiliary Diseases,Affiliated Hospital of Youjiang Medical College for Nationalities(GxZDSYs-009)Scientific Research and Technology Development Program of Baise City(Baike 20213301)Scientific Research and Technology Development Program of Baise City(Baike 20213242)Self-funded research project of Health Commission of Guangxi Zhuang Autonomous Region(20190953)Self-funded research Project of Administration of Traditional Chinese Medicine of Guangxi Zhuang Autonomous Region(GXZYL20220304)Guangxi University Young and Middle-aged Teachers Basic Research Ability Improvement Project(2021KY0538)。
文摘Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR,and mir-3168 mimic,inhibitor and negative control were synthesized.They were transfected into AGS and AGS/DDP gastric cancer cells,respectively.The expression of mir-3168 and TP53 mRNA was detected by qPCR.Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment,apoptosis was detected by flow cytometry,cell invasion was detected by Transwell,and TP53 protein expression was detected by western blot,The database predicted the binding sites of mir-3168 and TP53.According to the binding sites,the double luciferase experiment was used to verify the binding of mir-3168 and TP53.Results:Compared with cisplatin sensitive gastric cancer cell AGS,mir-3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP;mir-3168 mimic promotes cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 inhibitor inhibits cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and promotes apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 mimic inhibits the expression of TP53 mRNA and protein,and mir-3168 inhibitor promotes the expression of TP53 mRNA and protein;Targetscan database predicted that there was a binding point between mir-3168 and TP53,and the double luciferase experiment suggested that mir-3168 was bound to TP53 through the predicted binding site.Conclusion:mir-3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.
基金the Japan Society for the Promotion of Science(JSPS),KAKENHI,Grant Number 26350974.
文摘Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.
基金supported by the National Natural Science Foundation of China(No.81703001)the Natural Science Foundation of Hebei Province(No.H2021406021),Hebei Province Medical Science Research Project(Nos.20210247,20221335)Hebei Province Government-Funded Clinical Medical Outstanding Talents Project,Chengde Medical University Scientific Research Major Projects(No.KY2020005).
文摘The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.
基金supported by Academic Leader Training Program of Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13).
文摘The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.
基金supported by National Key Research and Development Program of China(2018YFA0108500)NSFC82341006,81673334,31970740,31801144,31800684 and 31701227+3 种基金Natural Science Foundation of Beijing(IS23071)Postdoctoral Research Foundation of China(2021M703206)Natural Science Foundation of Shanxi Province(202203021211155)the State Key Laboratory of Membrane Biology.
文摘Translesion DNA synthesis(TLS)can bypass DNA lesions caused by chemotherapeutic drugs,which usually result in drug resistance.Given its key role in mutagenesis and cell survival after DNA damage,inhibition of the TLS pathway has emerged as a potential target for improving the efficacy of DNA-damaging agents such as cisplatin(CDDP),a widely used anticancer agent.Unfortunately,few suitable natural TLS inhibitors have been reported.Here,we found that a triterpenoid compound Ganoboninketal C(26-3)from Ganoderma boninense,a traditional Chinese medicine,can impair CDDP-induced TLS polymerase eta(Polη)focus formation,PCNA monoubiquitination as well as mutagenesis.Moreover,26-3 can significantly sensitize tumor cells to CDDP killing and reduce the proportion of cancer stem cells in AGS and promote apoptosis after CDDP exposure.Interestingly,26-3 can also sensitize tumor cells to Gefitinib therapy.Mechanistically,through RNA-seq analysis,we found that 26-3 could abrogate the CDDP-induced upregulation of Polηand PIDD(p53-induced protein with a death domain),2 known factors promoting TLS pathway.Furthermore,we found that activating transcription factor 3 is a potential novel TLS modulator.Taken together,we have identified a natural TLS inhibitor 26-3,which can be potentially used as an adjuvant to improve clinical efficacy.
基金the Beijing Municipal Science and Technology Commission(grant Z211100002921013)the Tongzhou District Science and Technology Committee Project to Tongzhou(grant KJ2020CX010).
文摘Celecoxib,a cyclooxygenase-2 inhibitor,can enhance the efficacy of chemotherapy;however,its effect seems inconsistent.In this study,we investigated whether celecoxib would increase the antiproliferative effects of cisplatin in human lung cancer cells.Our data demonstrated the synergistic effects of celecoxib with cisplatin in wild-type p53 cells and their antagonistic effects inmutated or deleted p53 cells.Combination indices of 0.82 to 0.93 reflected a synergistic effect between celecoxib and cisplatin in lung cancer cells with wild-type p53.Combination indices of 1.63 to 3.00 reflected antagonism between celecoxib and cisplatin in lung cancer cells with mutated or deleted p53.Compared with that in cells with mutated or deleted p53,apoptosis significantly increased with the addition of celecoxib and cisplatin in wild-type p53 cells(P<0.05).Moreover,the results in vivo were similar to those in vitro:celecoxib combinedwith cisplatin slowed tumor growth in wild-type p53 groups and not in mutated or deleted p53 groups.In addition,celecoxib promoted p53 translocation into the nucleus and upregulated active p53 expression in wild-type p53 cells.Celecoxib combined with cisplatin upregulated PUMA(PUMA is a downstream gene of p53)after active p53 increased in wild-type p53 cells.In summary,the combination of celecoxib and cisplatin demonstrates clear synergistic effects in wild-type p53 cells and antagonistic effects inmutated or deleted p53 cells.The synergistic effect was achieved by apoptosis,induced by upregulating PUMA.Our results will provide a new treatment strategy for patients carrying wild-type p53,insensitive to cisplatin.
基金supported by the National Natural Science Foundation of China(No.82160386)the Guangxi Natural Science Foundation of China(No.2024GXNSFDA010032,2023GXNSFAA026189).
文摘Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent,cisplatin,is diminished in patients with poor prognoses.Methods:Various bioinformatics databases were utilized to examine Carboxylesterase 1(CES1)gene expression,clinicopathologic features,patient survival analysis,and gene function.An organoid model of HNSCC was established,along with the induction of drug-resistant HNSCC in the organoid model.CES1 expression was assessed using qRT-PCR and Western Blot,and differential markers were identified through transcriptome sequencing.Knockdown and overexpression models of CES1 were created in SCC-9 and patient-derived organoid(PDO)cells using shRNA and lentivirus to investigate the tumor biology and cisplatin resistance associated with CES1.Results:Research in bioinformatics has uncovered a strong correlation between the expression level of CES1 and the prognosis of HNSCC.The data suggests a significant link between CES1 expression and tobacco smoking.RNA-sequencing revealed a notable increase in CES1 expression in HNSCC-PDOcis-R cells compared to the parental PDO cells.Subsequently,we performed in vitro studies by HNSCC-PDO and SCC-9 and found that CES1-overexpressing cells exhibited reduced sensitivity to cisplatin and stronger tumor malignant biological behavior compared with CES1-knockdown cells.Conclusion:The observed association between CES1 expression and tobacco smoking implies a potential influence of smoking on the efficacy of cisplatin-based chemotherapy in HNSCC through the regulation of CES1 expression.
