微小RNA与胰腺癌化疗耐药的研究进展
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摘要
胰腺癌是一种消化道恶性肿瘤,其5年存活率低于6%。现有的药物治疗不能大幅度提高患者应答率。因此,深入了解治疗失败背后的机制,克服化疗耐受是亟需解决的问题。微小RNA(miRNA)是一类内生的、保守的、长度约为22个核苷酸的非编码RNA,具有翻译水平调控基因表达的功能。近年来,越来越多的研究表明miRNA的表达上调或下调可作用于不同的靶点或通路进而影响胰腺癌的发生、发展、预后和对治疗药物的耐受。通过miRNA的再表达或者抑制其过表达可以提高胰腺癌细胞对化疗药物的敏感,其模拟物或抑制剂均有望成为未来治疗胰腺癌的靶向药物。本文旨在对参与调控胰腺癌化疗耐受的miRNA进行总结,为临床治疗胰腺癌寻找新的靶向治疗方案。
Pancreatic cancer is the malignant tumor of digestive tract,which has a 5-year survival rate of less than6%.So far,the drug treatments are still not able to improve patient response rate significantly.Therefore,it is urgent to understand the mechanism behind the failure of treatment and to overcome the problem of chemo-resistance.The micro-RNA(miRNA) is a class of the endogenous noncoding RNA with about 22 nucleotides,which has the function of regulating gene expression at translation level.Recent researches showed that the upregulated or downregulated expression of miRNA can affect the occurrence and metastasis of pancreatic cancer and its chemo-resistance.Therefore,to regulate miRNA expression can increase the sensitivity of pancreatic cancer cells to chemotherapies.In the future,the miRNA analogues or its inhibitors might be developed as targeted drugs for the treatment of pancreatic cancer.This paper summarizes the miRNA involved in the chemotherapy resistance of pancreatic cancer,and its application to find new targeted drug of pancreatic cancer.
Pancreatic cancer is the malignant tumor of digestive tract,which has a 5-year survival rate of less than6%.So far,the drug treatments are still not able to improve patient response rate significantly.Therefore,it is urgent to understand the mechanism behind the failure of treatment and to overcome the problem of chemo-resistance.The micro-RNA(miRNA) is a class of the endogenous noncoding RNA with about 22 nucleotides,which has the function of regulating gene expression at translation level.Recent researches showed that the upregulated or downregulated expression of miRNA can affect the occurrence and metastasis of pancreatic cancer and its chemo-resistance.Therefore,to regulate miRNA expression can increase the sensitivity of pancreatic cancer cells to chemotherapies.In the future,the miRNA analogues or its inhibitors might be developed as targeted drugs for the treatment of pancreatic cancer.This paper summarizes the miRNA involved in the chemotherapy resistance of pancreatic cancer,and its application to find new targeted drug of pancreatic cancer.
引文
[1]李骥.胰腺癌和肿瘤多药耐药(文献综述)[J].国外医学.外科学分册,2004,31(2):69-72.
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[11]Humeau M,Torrisani J,Cordelier P.miRNA in clinical practice:pancreatic cancer[J].Clin Biochem,2013,46(10-11):933-936.
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[21]Song W,Wang L,Huang W,et al.MiR-21 upregulation induced by promoter zone histone acetylation is associated with chemoresistance to gemcitabine and enhanced malignancy of pancreatic cancer cells[J].Asian Pac J Cancer Prev,2013,14(12):7529-7536.
[22]Dentelli P,Traversa M,Rosso A,et al.miR-221/222 control luminal breast cancer tumor progression by regulating different targets[J].Cell Cycle,2014,13(11):1811-1826.
[23]Wang L,Liu C,Li C,et al.Effects of microRNA-221/222 on cell proliferation and apoptosis in prostate cancer cells[J].Gene,2015,572(2):252-258.
[24]Amini-Farsani Z,Sangtarash MH,Shamsara M,et al.MiR-221/222 promote chemoresistance to cisplatin in ovarian cancer cells by targeting PTEN/PI3K/AKT signaling pathway[J].Cytotechnology,2018,70(1):203-213.
[25]Xu Q,Li P,Chen X,et al.miR-221/222 induces pancreatic cancer progression through the regulation of matrix metalloproteinases[J].Oncotarget,2015,6(16):14153-14164.
[26]Sarkar S,Dubaybo H,Ali S,et al.Down-regulation of miR-221inhibits proliferation of pancreatic cancer cells through upregulation of PTEN,p27kip1,p57kip2,and PUMA[J].Am JCancer Res,2013,3(5):465-477.
[27]Zhao L,Zou D,Wei X,et al.MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1[J].Tumor Biology,2016,37(12):16053-16063.
[28]Faneca H,Passadouro M,Pedroso De Lima M.MicroRNAmodulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer[J].Int J Nanomedicine,2014,9:3203-3217.
[29]Wong MYW,Yu Y,Walsh WR,et al.microRNA-34 family and treatment of cancers with mutant or wild-type p53(Review)[J].Int J Oncol,2011,38(5):11 89-11 95.
[30]Vogt M,Munding J,Grüner M,et al.Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal,pancreatic,mammary,ovarian,urothelial,and renal cell carcinomas and soft tissue sarcomas[J].Virchows Arch,2011,458(3):313-322.
[31]Jafari N,Abediankenari S.MicroRNA-34 dysregulation in gastric cancer and gastric cancer stem cell[J].Tumor Biol,2017,39(5):568835531-568835531.
[32]Zeng Z,Chen X,Zhu D,et al.Low expression of circulating MicroRNA-34c is associated with poor prognosis in triplenegative breast cancer[J].Yonsei Med J,2017,58(4):697-702.
[33]Stahlhut C,Slack FJ.Combinatorial action of MicroRNAslet-7and miR-34 effectively synergizes with erlotinib to suppress non-small cell lung cancer cell proliferation[J].Cell Cycle,2015,14(13):2171-2180.
[34]Zhao K,Cheng J,Chen B,et al.Circulating microRNA-34family low expression correlates with poor prognosis in patients with non-small cell lung cancer[J].J Thorac Dis,2017,9(10):3735-3746.
[35]Ji Q,Hao X,Zhang M,et al.MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells[J].PLoS One,2009,4(8):e6816-e6816.
[36]Zhang Q,Yang X,Chen D,et al.miR-34 increases in vitro PANC-1 cell sensitivity to gemcitabine via targeting Slug/PUMA[J].Cancer Biomark,2018,21(4):755-762.
[37]Humphries B,Yang C.The microRNA-200 family:small molecules with novel roles in cancer development,progression and therapy[J].Oncotarget,2015,6(9):6472-6498.
[38]Zhou J,Zhang L,Zhang T,et al.Dysregulation of miR-200s clusters as potential prognostic biomarkers in acute myeloid leukemia[J].J Transl Med,2018,16(1):135-135.
[39]San K,Horita M,Ganapathy A,et al.Deregulated expression of microRNA-200b/c and SUZ12,a polycomb repressive complex 2 subunit,in chemoresistant colorectal cancer cells[J].Genes Cancer,2017,8(7-8):673-673.
[40]Mekala JR,Naushad SM,Ponnusamy L,et al.Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer[J].Gene,2018,641:248-258.
[41]Dykxhoorn DM.MicroRNAs and metastasis:little rnas go a long way[J].Cancer Res,2010,70(16):6401-6406.
[42]Ma C,Huang T,Ding Y C,e t al.Mi c roRNA-200c overexpression inhibits chemoresistance,invasion and colony formation of human pancreatic cancer stem cells[J].Int J Clin Exp Pathol,2015,8(6):6533-6539.
[43]Singh S,Chitkara D,Kumar V,et al.miRNA profiling in pancreatic cancer and restoration of chemosensitivity[J].Cancer Lett,2013,334(2):211-220.
[44]Chaudhary AK,Mondal G,Kumar V,et al.Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205[J].Cancer Lett,2017,402:1-8.
[45]Wang P,Zhu CF,Ma MZ,et al.Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer[J].Oncotarget,2015,6(25):211 48-211 58.
[46]Taucher V,Mangge H,Haybaeck J.Non-coding RNAs in pancreatic cancer:challenges and opportunities for clinical application[J].Cellr Oncol l(Dordr),2016,39(4):295-318.
[47]Richards KE,Zeleniak AE,Fishel ML,et al.Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells[J].Oncogene,2017,36(13):1770-1778.
[48]Schreiber R,Mezencev R,Matyunina LV,et al.Evidence for the role of microRNA 374b in acquired cisplatin resistance in pancreatic cancer cells[J].Cancer Gene Ther,2016,23(8):241-245.
[49]Lin Y,Ge X,Wen Y,et al.MiRNA-145 increases therapeutic sensibility to gemcit abinetreatment of pancreatic adenocarcinoma cells[J].Oncotarget,2016,7(43):70857-70857.
[50]Cioffi M,Trabulo SM,Sanchez-Ripoll Y,et al.The miR-17-92cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells[J].Gut,2015,64(12):1936-1948.
[51]Takiuchi D,Eguchi H,Nagano H,et al.Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells[J].Pancreatology,2013,13(5):517-523.
[52]Chen M,Wang M,Xu S,et al.Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway[J].Oncotarget,2015,6(42):44466-44479.
[53]Hasegawa S,Eguchi H,Nagano H,et al.MicroRNA-1246expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer[J].Br J Cancer,2014,111(8):1572-1580.
[2]Cui JJ,Jiang WH,Wang SY,et al.Role of Wnt/-catenin signaling in drug resistance of pancreatic cancer[J].Curr Pharm Des,2012,18(17):2464-2471.
[3]Uwagawa T,Yanaga K.Effect of NF-κB inhibition on chemoresistance in biliary-pancreatic cancer[J].Surg Today,2015,45(12):1481-1488.
[4]Yao J,Zhang P,Li J,et al.MicroRNA-215 acts as a tumor suppressor in breast cancer by targeting AKT serine/threonine kinase 1[J].Oncol Lett,2017,14(1):1097-11 04.
[5]Lee EJ,Gusev Y,Jiang J,et al.Expression profiling identifies microRNA signature in pancreatic cancer[J].Int J Cancer,2007,120(5):1046-1054.
[6]Wang J,Chen J,Chang P,et al.MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel bloodbased biomarkers of disease[J].Cancer Prev Res,2009,2(9):807-813.
[7]Bloomston M,Frankel WL,Petrocca F,et al.MicroRNAexpression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis[J].J Am Med Assoc,2007,97(17):1901-1908.
[8]Giovannetti E,Funel N,Peters G J,et al.MicroRNA-21in pancreatic cancer:correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity[J].Cancer Res,2010,70(11):4528-4538.
[9]Sicard F,Gayral M,Lulka H,et al.Targeting miR-21 for the therapy of pancreatic cancer[J].Mol Ther,2013,21(5):986-994.
[10]Khan S,Ansarullah,Kumar D,et al.Targeting microRNAs in pancreatic cancer:microplayers in the big game[J].Cancer Res,2013,73(22):6541-6547.
[11]Humeau M,Torrisani J,Cordelier P.miRNA in clinical practice:pancreatic cancer[J].Clin Biochem,2013,46(10-11):933-936.
[12]Kadera BE,Li L,Toste PA,et al.MicroRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promotes metastasis[J].PLoS One,2013,8(8):e71978-e71978.
[13]Zhang J,Zhang C,Hu L,et al.Abnormal expression of miR-21 and miR-95 in cancer stem-like cells is associated with radioresistance of lung cancer[J].Cancer Invest,2015,33(5):165-171.
[14]Najafi Z,Sharifi M,Javadi G.Degradation of miR-21 induces apoptosis and inhibits cell proliferation in human hepatocellular carcinoma[J].Cancer Gene Ther,2015,22(11):530-535.
[15]Xu L,Huang Y,Chen D,et al.Downregulation of miR-21increases cisplatin sensitivity of non-small-cell lung cancer[J].Cancer Genet,2014,207(5):214-220.
[16]Moriyama T,Ohuchida K,Mizumoto K,et al.MicroRNA-21modulates biological functions of pancreatic cancer cells including their proliferation,invasion,and chemoresistance[J].Mol Cancer Ther,2009,8(5):1067-1074.
[17]Zhao Y,Zhao L,Ischenko I,et al.Antisense inhibition of microRNA-21 and microRNA-221 in tumor-initiating stem-like cells modulates tumorigenesis,metastasis,and chemotherapy resistance in pancreatic cancer[J].Target Oncol,2015,10(4):535-548.
[18]Hwang JH,Voortman J,Giovannetti E,et al.Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer[J].PLoS One,2010,5(5):e10630.
[19]Wang P,Zhuang L,Zhang J,et al.The serum miR-21level serves as a predictor for the chemosensitivity of advanced pancreatic cancer,and miR-21 expression confers chemoresistance by targeting FasL[J].Mol Oncol,2013,7(3):334-345.
[20]Dong J,Zhao Y,Zhou L,et al.Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells[J].Arch Med Res,2011,42(1):8-14.
[21]Song W,Wang L,Huang W,et al.MiR-21 upregulation induced by promoter zone histone acetylation is associated with chemoresistance to gemcitabine and enhanced malignancy of pancreatic cancer cells[J].Asian Pac J Cancer Prev,2013,14(12):7529-7536.
[22]Dentelli P,Traversa M,Rosso A,et al.miR-221/222 control luminal breast cancer tumor progression by regulating different targets[J].Cell Cycle,2014,13(11):1811-1826.
[23]Wang L,Liu C,Li C,et al.Effects of microRNA-221/222 on cell proliferation and apoptosis in prostate cancer cells[J].Gene,2015,572(2):252-258.
[24]Amini-Farsani Z,Sangtarash MH,Shamsara M,et al.MiR-221/222 promote chemoresistance to cisplatin in ovarian cancer cells by targeting PTEN/PI3K/AKT signaling pathway[J].Cytotechnology,2018,70(1):203-213.
[25]Xu Q,Li P,Chen X,et al.miR-221/222 induces pancreatic cancer progression through the regulation of matrix metalloproteinases[J].Oncotarget,2015,6(16):14153-14164.
[26]Sarkar S,Dubaybo H,Ali S,et al.Down-regulation of miR-221inhibits proliferation of pancreatic cancer cells through upregulation of PTEN,p27kip1,p57kip2,and PUMA[J].Am JCancer Res,2013,3(5):465-477.
[27]Zhao L,Zou D,Wei X,et al.MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1[J].Tumor Biology,2016,37(12):16053-16063.
[28]Faneca H,Passadouro M,Pedroso De Lima M.MicroRNAmodulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer[J].Int J Nanomedicine,2014,9:3203-3217.
[29]Wong MYW,Yu Y,Walsh WR,et al.microRNA-34 family and treatment of cancers with mutant or wild-type p53(Review)[J].Int J Oncol,2011,38(5):11 89-11 95.
[30]Vogt M,Munding J,Grüner M,et al.Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal,pancreatic,mammary,ovarian,urothelial,and renal cell carcinomas and soft tissue sarcomas[J].Virchows Arch,2011,458(3):313-322.
[31]Jafari N,Abediankenari S.MicroRNA-34 dysregulation in gastric cancer and gastric cancer stem cell[J].Tumor Biol,2017,39(5):568835531-568835531.
[32]Zeng Z,Chen X,Zhu D,et al.Low expression of circulating MicroRNA-34c is associated with poor prognosis in triplenegative breast cancer[J].Yonsei Med J,2017,58(4):697-702.
[33]Stahlhut C,Slack FJ.Combinatorial action of MicroRNAslet-7and miR-34 effectively synergizes with erlotinib to suppress non-small cell lung cancer cell proliferation[J].Cell Cycle,2015,14(13):2171-2180.
[34]Zhao K,Cheng J,Chen B,et al.Circulating microRNA-34family low expression correlates with poor prognosis in patients with non-small cell lung cancer[J].J Thorac Dis,2017,9(10):3735-3746.
[35]Ji Q,Hao X,Zhang M,et al.MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells[J].PLoS One,2009,4(8):e6816-e6816.
[36]Zhang Q,Yang X,Chen D,et al.miR-34 increases in vitro PANC-1 cell sensitivity to gemcitabine via targeting Slug/PUMA[J].Cancer Biomark,2018,21(4):755-762.
[37]Humphries B,Yang C.The microRNA-200 family:small molecules with novel roles in cancer development,progression and therapy[J].Oncotarget,2015,6(9):6472-6498.
[38]Zhou J,Zhang L,Zhang T,et al.Dysregulation of miR-200s clusters as potential prognostic biomarkers in acute myeloid leukemia[J].J Transl Med,2018,16(1):135-135.
[39]San K,Horita M,Ganapathy A,et al.Deregulated expression of microRNA-200b/c and SUZ12,a polycomb repressive complex 2 subunit,in chemoresistant colorectal cancer cells[J].Genes Cancer,2017,8(7-8):673-673.
[40]Mekala JR,Naushad SM,Ponnusamy L,et al.Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer[J].Gene,2018,641:248-258.
[41]Dykxhoorn DM.MicroRNAs and metastasis:little rnas go a long way[J].Cancer Res,2010,70(16):6401-6406.
[42]Ma C,Huang T,Ding Y C,e t al.Mi c roRNA-200c overexpression inhibits chemoresistance,invasion and colony formation of human pancreatic cancer stem cells[J].Int J Clin Exp Pathol,2015,8(6):6533-6539.
[43]Singh S,Chitkara D,Kumar V,et al.miRNA profiling in pancreatic cancer and restoration of chemosensitivity[J].Cancer Lett,2013,334(2):211-220.
[44]Chaudhary AK,Mondal G,Kumar V,et al.Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205[J].Cancer Lett,2017,402:1-8.
[45]Wang P,Zhu CF,Ma MZ,et al.Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer[J].Oncotarget,2015,6(25):211 48-211 58.
[46]Taucher V,Mangge H,Haybaeck J.Non-coding RNAs in pancreatic cancer:challenges and opportunities for clinical application[J].Cellr Oncol l(Dordr),2016,39(4):295-318.
[47]Richards KE,Zeleniak AE,Fishel ML,et al.Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells[J].Oncogene,2017,36(13):1770-1778.
[48]Schreiber R,Mezencev R,Matyunina LV,et al.Evidence for the role of microRNA 374b in acquired cisplatin resistance in pancreatic cancer cells[J].Cancer Gene Ther,2016,23(8):241-245.
[49]Lin Y,Ge X,Wen Y,et al.MiRNA-145 increases therapeutic sensibility to gemcit abinetreatment of pancreatic adenocarcinoma cells[J].Oncotarget,2016,7(43):70857-70857.
[50]Cioffi M,Trabulo SM,Sanchez-Ripoll Y,et al.The miR-17-92cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells[J].Gut,2015,64(12):1936-1948.
[51]Takiuchi D,Eguchi H,Nagano H,et al.Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells[J].Pancreatology,2013,13(5):517-523.
[52]Chen M,Wang M,Xu S,et al.Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway[J].Oncotarget,2015,6(42):44466-44479.
[53]Hasegawa S,Eguchi H,Nagano H,et al.MicroRNA-1246expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer[J].Br J Cancer,2014,111(8):1572-1580.