miRNA Let-7与乳腺癌预后的相关性分析
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摘要
目的探讨Let-7家族各成员与乳腺癌患者预后相关性,寻找更有效的乳腺癌防治分子靶标。方法利用KaplanMeier plotter在线数据库分析Let-7家族各成员(Let-7a、7b、7c、7d、7e、7f、7g、7i、miR-98、miR-202)表达与乳腺癌患者总生存期(OS)及临床病理参数的相关性,并得出相应的危险比(HR)、95%置信区间(CI)和P值。结果 Let-7a、Let-7b、Let-7c、Let-7e、Let-7f、Let-7g、miR-98高表达或miR-202低表达的患者有较好的OS(P<0.05);病理特征分析显示,Let-7a、Let-7b、Let-7f、Let-7g、miR-98、miR-202的表达与疾病临床分期存在相关性(P<0.05)。Let-7a、Let-7b、Let-7c、Let-7e、Let-7f、Let-7g、miR-98和miR-202与淋巴结表达存在相关性(P<0.05);三阴乳腺癌患者OS则与Let-7b、Let-7c、Let-7g、miR-202表达显著相关(P<0.05)。结论 Let-7与乳腺癌患者OS显著相关,各成员在乳腺癌中的预后判断中具有不同的价值,其中Let-7b、Let-7g、miR-202在不同临床参数及三阴乳腺癌中都显示出与预后密切相关,更有望成为乳腺癌防治靶标。
Objective To explore the expression of miRLet-7 family members in breast cancer and its correlation with overall survivals(OS),and to find more effective molecular targets for breast cancer prevention and treatment.Methods Kaplan-Meier(KM) plotter online database was used to analyze the correlation among the expression of Let-7 family members(Let-7a,7b,7c,7d,7e,7f,7g,7i,miR-98,miR-202) correlated with overall survival(OS) and the prognosis and clinical pathological parameters of breast cancer patients,and Hazard ratio(HR),95% confidence interval(CI),and P value were determined.Results The study showed that the high expression level of Let-7a,Let-7b,Let-7c,Let-7e,Let-7f,Let-7g,miR-98 and the low expression level of miR-202 was associated with better OS for breast cancer patients(P<0.05).We further assessed the prognostic value of Let-7in different subtypes and clinical stage.The expression of Let-7a,Let-7b,Let-7f,Let-7g,miR-98,miR-202 was related to clinical stage(P<0.05).Let-7a,Let-7b,Let-7c,Let-7e,Let-7f,Let-7g,miR-98 and miR-202 was related to lymph node status(P<0.05).In triple-negative breast cancers(TNBC),with breast cancer subtype,the expression of Let-7b,Let-7c,Let-7g and miR-202 was significantly correlated to overall survival(P<0.05).Conclusion The Let-7 is significantly correlated with OS in breast cancer patients.The results suggested that members of the Let-7 have different values in predicting the prognosis of breast cancer.Among them,Let-7b,Let-7g and miR-202 are closely related with clinical stage and TNBC,and might promote development of Let-7as targeted inhibitors for the treatment of breast cancer.
Objective To explore the expression of miRLet-7 family members in breast cancer and its correlation with overall survivals(OS),and to find more effective molecular targets for breast cancer prevention and treatment.Methods Kaplan-Meier(KM) plotter online database was used to analyze the correlation among the expression of Let-7 family members(Let-7a,7b,7c,7d,7e,7f,7g,7i,miR-98,miR-202) correlated with overall survival(OS) and the prognosis and clinical pathological parameters of breast cancer patients,and Hazard ratio(HR),95% confidence interval(CI),and P value were determined.Results The study showed that the high expression level of Let-7a,Let-7b,Let-7c,Let-7e,Let-7f,Let-7g,miR-98 and the low expression level of miR-202 was associated with better OS for breast cancer patients(P<0.05).We further assessed the prognostic value of Let-7in different subtypes and clinical stage.The expression of Let-7a,Let-7b,Let-7f,Let-7g,miR-98,miR-202 was related to clinical stage(P<0.05).Let-7a,Let-7b,Let-7c,Let-7e,Let-7f,Let-7g,miR-98 and miR-202 was related to lymph node status(P<0.05).In triple-negative breast cancers(TNBC),with breast cancer subtype,the expression of Let-7b,Let-7c,Let-7g and miR-202 was significantly correlated to overall survival(P<0.05).Conclusion The Let-7 is significantly correlated with OS in breast cancer patients.The results suggested that members of the Let-7 have different values in predicting the prognosis of breast cancer.Among them,Let-7b,Let-7g and miR-202 are closely related with clinical stage and TNBC,and might promote development of Let-7as targeted inhibitors for the treatment of breast cancer.
引文
[1]Siegel RL,Miller KD,Jemal A.Cancer statistics 2015[J].CA Cancer JClin,2015,65(1):5-29.doi:10.3322/caac.21254.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China 2015[J].CA Cancer J Clin,2016,66(2):115-132.doi:10.3322/caac.21338.
[3]Raisch J,Darfeuillemichaud A,Nguyen HT,et al.Role of microRNAs in the immune system,inflammation and cancer[J].World J Gastroenterol,2013,19(20):2985-2996.doi:10.3748/wjg.v19.i20.2985.
[4]Chiu SC,Chung HY,Cho DY,et al.Therapeutic potential of microRNAlet-7:tumor suppression or impeding normal stemness[J].Cell Transplant,2014,23(4-5):459-469.doi:10.3727/096368914X678418.
[5]Qattan A,Intabli H,Alkhayal W,et al.Robust expression of tumor suppressor miRNA's let-7 and miR-195 detected in plasma of Saudi female breast cancer patients[J].BMC Cancer,2017,17(1):799.doi:10.1186/s12885-017-3776-5.
[6]Sun H,Ding C,Zhang H,et al.Let7 miRNAs sensitize breast cancer stem cells to radiationinduced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway[J].Mol Med Rep,2016,14(4):3285-3292.doi:10.3892/mmr.2016.5656.
[7]Liu Y,Cui J,Tang YL,et al.Prognostic roles of mRNA expression of S100 in non-small-cell lung cancer[J].Biomed Res Int,2018(21):9815806.doi:10.1155/2018/9815806.
[8]Thammaiah CK,Jayaram S.Role of let-7 family microRNA in breast cancer[J].Noncoding RNA Res,2016,1(1):77-82.doi:10.1016/j.ncrna.2016.10.003.
[9]Yu F,Yao H,Zhu P,et al.let-7 regulates self renewal and tumorigenicity of breast cancer cells[J].Cell,2007,131(6):1109-1123.doi:10.1016/j.cell.2007.10.054.
[10]Lagendijk M,Sadaatmand S,Koppert LB,et al.MicroRNA expression in pre-treatment plasma of patients with benign breast diseases and breast cancer[J].Oncotarget,2018,9(36):24335-24346.doi:10.18632/oncotarget.25262.
[11]Al-Harbi B,Hendrayani SF,Silva G,et al.Let-7b inhibits cancerpromoting effects of breast cancer-associated fibroblasts through IL-8repression[J].Oncotarget,2018,9(25):17825-17838.doi:10.18632/oncotarget.24895.
[12]Hu X,Guo J,Zheng L,et al.The heterochronic microRNA let-7 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway in breast cancer[J].Mol Cancer Res,2013,11(3):240-250.doi:10.1158/1541-7786.
[13]Wang L,Li M,Zhou Y,et al.MicroRNA Let-7g directly targets forkhead box C2(FOXC2)to modulate bone metastasis in breast cancer[J].Open Med(Wars),2017,12(1):157-162.doi:10.1515/med-2017-0023.
[14]Siragam V,Rutnam ZJ,Yang W,et al.MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11[J].Oncotarget,2012,3(11):1370-1385.doi:10.18632/oncotarget.717.
[15]Joosse SA,Müller V,Steinbach B,et al.Circulating cell-free cancertestis MAGE-A RNA,BORIS RNA,let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases[J].Br JCancer,2014,111(5):909-917.doi:10.1038/bjc.2014.360.
[16]Sun X,Xu C,Xiao G,et al.Breast cancer stem-like cells are sensitized to tamoxifen induction of self-renewal inhibition with enforced Let-7c dependent on Wnt blocking[J].Int J Mol Med,2018,41(4):1967-1975.doi:10.3892/ijmm.2018.3388.
[17]Lv J,Xia K,Xu P,et al.Biomed Pharmacother.miRNA expression patterns in chemoresistant breast cancer tissues[J].Biomed Pharmacother,2014,68(8):935-942.doi:10.1016/j.biopha.2014.09.011.
[18]Shibahara Y,Miki Y,Onodera Y,et al.Aromatase inhibitor treatment of breast cancer cells increases the expression of let-7f,a microRNA targeting CYP19A1[J].J Pathol,2012,227(3):357-366.doi:10.1002/path.4019.
[19]Wu K,Yang Y,Zhao J,et al.BAG3-mediated miRNA let-7g and let-7i inhibit proliferation and enhance apoptosis of human esophageal carcinoma cells by targeting the drug transporter ABCC10[J].Cancer Lett,2016,371(1):125-133.doi:10.1016/j.canlet.2015.11.031.
[20]Xiang Q,Tang H,Yu J,et al.MicroRNA-98 sensitizes cisplatin-resistant human lung adenocarcinoma cells by up-regulation of HMGA2[J].Pharmazie,2013,68(4):274-281.doi:10.1691/ph.2013.2759.
[21]Sun X,Qin S,Fan C,et al.Let-7:a regulator of the ERαsignaling pathway in human breast tumors and breast cancer stem cells[J].Oncol Rep,2013,29(5):2079-2087.doi:10.3892/or.2013.2330.
[22]Chiu HW,Lin HY,Tseng IJ,et al.OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast cancer[J].Oncotarget,2017,9(1):553-565.doi:10.18632/oncotarget.23074.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China 2015[J].CA Cancer J Clin,2016,66(2):115-132.doi:10.3322/caac.21338.
[3]Raisch J,Darfeuillemichaud A,Nguyen HT,et al.Role of microRNAs in the immune system,inflammation and cancer[J].World J Gastroenterol,2013,19(20):2985-2996.doi:10.3748/wjg.v19.i20.2985.
[4]Chiu SC,Chung HY,Cho DY,et al.Therapeutic potential of microRNAlet-7:tumor suppression or impeding normal stemness[J].Cell Transplant,2014,23(4-5):459-469.doi:10.3727/096368914X678418.
[5]Qattan A,Intabli H,Alkhayal W,et al.Robust expression of tumor suppressor miRNA's let-7 and miR-195 detected in plasma of Saudi female breast cancer patients[J].BMC Cancer,2017,17(1):799.doi:10.1186/s12885-017-3776-5.
[6]Sun H,Ding C,Zhang H,et al.Let7 miRNAs sensitize breast cancer stem cells to radiationinduced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway[J].Mol Med Rep,2016,14(4):3285-3292.doi:10.3892/mmr.2016.5656.
[7]Liu Y,Cui J,Tang YL,et al.Prognostic roles of mRNA expression of S100 in non-small-cell lung cancer[J].Biomed Res Int,2018(21):9815806.doi:10.1155/2018/9815806.
[8]Thammaiah CK,Jayaram S.Role of let-7 family microRNA in breast cancer[J].Noncoding RNA Res,2016,1(1):77-82.doi:10.1016/j.ncrna.2016.10.003.
[9]Yu F,Yao H,Zhu P,et al.let-7 regulates self renewal and tumorigenicity of breast cancer cells[J].Cell,2007,131(6):1109-1123.doi:10.1016/j.cell.2007.10.054.
[10]Lagendijk M,Sadaatmand S,Koppert LB,et al.MicroRNA expression in pre-treatment plasma of patients with benign breast diseases and breast cancer[J].Oncotarget,2018,9(36):24335-24346.doi:10.18632/oncotarget.25262.
[11]Al-Harbi B,Hendrayani SF,Silva G,et al.Let-7b inhibits cancerpromoting effects of breast cancer-associated fibroblasts through IL-8repression[J].Oncotarget,2018,9(25):17825-17838.doi:10.18632/oncotarget.24895.
[12]Hu X,Guo J,Zheng L,et al.The heterochronic microRNA let-7 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway in breast cancer[J].Mol Cancer Res,2013,11(3):240-250.doi:10.1158/1541-7786.
[13]Wang L,Li M,Zhou Y,et al.MicroRNA Let-7g directly targets forkhead box C2(FOXC2)to modulate bone metastasis in breast cancer[J].Open Med(Wars),2017,12(1):157-162.doi:10.1515/med-2017-0023.
[14]Siragam V,Rutnam ZJ,Yang W,et al.MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11[J].Oncotarget,2012,3(11):1370-1385.doi:10.18632/oncotarget.717.
[15]Joosse SA,Müller V,Steinbach B,et al.Circulating cell-free cancertestis MAGE-A RNA,BORIS RNA,let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases[J].Br JCancer,2014,111(5):909-917.doi:10.1038/bjc.2014.360.
[16]Sun X,Xu C,Xiao G,et al.Breast cancer stem-like cells are sensitized to tamoxifen induction of self-renewal inhibition with enforced Let-7c dependent on Wnt blocking[J].Int J Mol Med,2018,41(4):1967-1975.doi:10.3892/ijmm.2018.3388.
[17]Lv J,Xia K,Xu P,et al.Biomed Pharmacother.miRNA expression patterns in chemoresistant breast cancer tissues[J].Biomed Pharmacother,2014,68(8):935-942.doi:10.1016/j.biopha.2014.09.011.
[18]Shibahara Y,Miki Y,Onodera Y,et al.Aromatase inhibitor treatment of breast cancer cells increases the expression of let-7f,a microRNA targeting CYP19A1[J].J Pathol,2012,227(3):357-366.doi:10.1002/path.4019.
[19]Wu K,Yang Y,Zhao J,et al.BAG3-mediated miRNA let-7g and let-7i inhibit proliferation and enhance apoptosis of human esophageal carcinoma cells by targeting the drug transporter ABCC10[J].Cancer Lett,2016,371(1):125-133.doi:10.1016/j.canlet.2015.11.031.
[20]Xiang Q,Tang H,Yu J,et al.MicroRNA-98 sensitizes cisplatin-resistant human lung adenocarcinoma cells by up-regulation of HMGA2[J].Pharmazie,2013,68(4):274-281.doi:10.1691/ph.2013.2759.
[21]Sun X,Qin S,Fan C,et al.Let-7:a regulator of the ERαsignaling pathway in human breast tumors and breast cancer stem cells[J].Oncol Rep,2013,29(5):2079-2087.doi:10.3892/or.2013.2330.
[22]Chiu HW,Lin HY,Tseng IJ,et al.OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast cancer[J].Oncotarget,2017,9(1):553-565.doi:10.18632/oncotarget.23074.