miR-451a促进胰腺癌细胞对吉西他滨的敏感性
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摘要
目的:探究miR-451a在胰腺癌吉西他滨耐药中的功能。方法:通过低浓度梯度递增法建立胰腺癌吉西他滨耐药细胞株,microRNA(miRNA)测序筛选耐药相关miRNA;细胞存活曲线、克隆形成实验及流式凋亡实验分析miR-451a对胰腺癌细胞耐药的影响;裸鼠成瘤实验检测在动物体内模型中miR-451a对胰腺癌吉西他滨耐药的调控作用;调取TCGA数据分析miR-451a表达水平与胰腺癌病人预后的相关性。结果:胰腺癌吉西他滨耐药细胞株中miR-451a表达水平明显下调;miR-451a过表达增加胰腺癌细胞对吉西他滨的敏感性,增强了吉西他滨抑制细胞增殖和诱导细胞凋亡的作用;miR-451a诱导了裸鼠皮下肿瘤对吉西他滨敏感;miR-451a低表达与胰腺癌患者不良预后相关。结论:miR-451a增强了胰腺癌细胞对吉西他滨的敏感性。
Objective: To investigate the role of miR-451 a in gemcitabine resistance of pancreatic cancer. Methods: Gemcitabine-resistant cell line was established by exposing wild type cell line to gradually increasing dose of gemcitabine. miRNA sequencing was used to screen drug-resistance-related miRNAs. The cell viability assay,colony formation assay and apoptosis detection were utilized to analyze the effect of miR-451 a on gemcitabine sensitivity of pancreatic cancer cells. The xenografts in nude mice were used to detect the regulation of gemcitabine resistance by miR-451 a in vivo. The data from TCGA database was analyzed to reveal the correlation of miR-451 a level and prognosis of pancreatic cancer patients. Results: miR-451 a was downregulated in gemcitabine-resistant cell line. Overexpression of miR-451 a enhanced the sensitivity of pancreatic cancer cells to gemcitabine, inhibited cell proliferation and promoted cell apoptosis induced by gemcitabine. Same results were obtained in xenograft models. The database analysis confirmed that low level of miR-451 a was correlated to poor prognosis of pancreatic cancer patients. Conclusion: miR-451 a can enhance the sensitivity of pancreatic cancer cells to gemcitabine.
Objective: To investigate the role of miR-451 a in gemcitabine resistance of pancreatic cancer. Methods: Gemcitabine-resistant cell line was established by exposing wild type cell line to gradually increasing dose of gemcitabine. miRNA sequencing was used to screen drug-resistance-related miRNAs. The cell viability assay,colony formation assay and apoptosis detection were utilized to analyze the effect of miR-451 a on gemcitabine sensitivity of pancreatic cancer cells. The xenografts in nude mice were used to detect the regulation of gemcitabine resistance by miR-451 a in vivo. The data from TCGA database was analyzed to reveal the correlation of miR-451 a level and prognosis of pancreatic cancer patients. Results: miR-451 a was downregulated in gemcitabine-resistant cell line. Overexpression of miR-451 a enhanced the sensitivity of pancreatic cancer cells to gemcitabine, inhibited cell proliferation and promoted cell apoptosis induced by gemcitabine. Same results were obtained in xenograft models. The database analysis confirmed that low level of miR-451 a was correlated to poor prognosis of pancreatic cancer patients. Conclusion: miR-451 a can enhance the sensitivity of pancreatic cancer cells to gemcitabine.
引文
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[19]Pan X,Wang R,Wang Z X.The potential role of mi R-451 in cancer diagnosis,prognosis,and therapy[J].Mol Cancer Ther 2013,12(7):1153-1162.
[20]Zhang F,Huang W,Sheng M,et al.Mi R-451 inhibits cell growth and invasion by targeting CXCL16 and is associated with prognosis of osteosarcoma patients[J].Tumor Biol,2015,36(3):2041-2048.
[21]Liu N,Jiang N,Guo R,et al.Mi R-451 inhibits cell growth and invasion by targeting MIF and is associated with survival in nasopharyngeal carcinoma[J].Mol Cancer,2013,12(1):123-131.
[22]Fukumoto I,Kinoshita T,Hanazawa T,et al.Identification of tumour suppressive micro RNA-451a in hypopharyngeal squamous cell carcinoma based on micro R-NA expression signature[J].Br J Cancer,2014,111(2):386-394.
[23]Krakowsky R H E,Wurm A A,Gerloff D,et al.mi R-451a abrogates treatment resistance in FLT3-ITD-positive acute myeloid leukemia[J].Blood Cancer J,2018,8(3):36-40.
[24]Liu Z R,Song Y,Wan L H,et al.Over-expression of mi R-451a can enhance the sensitivity of breast cancer cells to tamoxifen by regulating 14-3-3ζ,estrogen receptorα,and autophagy[J].Life Sci,2016,149:104-113.
[25]Bitarte N,Bandres E,Boni V,et al.Micro RNA-451is involved in the self-renewal,tumorigenicity,and chemoresistance of colorectal cancer stem cells[J].Stem Cells,2011,29(11):1661-1671.
[26]Nan Y,Han L,Zhang A,et al.Mi RNA-451 plays a role as tumor suppressor in human glioma cells[J].Brain Res,2010,1359:14-21.
[27]Chang C,Liu J,He W.A regulatory circuit HP1γ/mi R-451a/c-Myc promotes prostate cancer progression[J].Oncogene,2017,37(4):415-426.
[2]Michl P,Gress T M.Current concepts and novel targets in advanced pancreatic cancer[J].Gut,2013,62(2):317-326.
[3]Oettle H.Progress in the knowledge and treatment of advanced pancreatic cancer:From benchside to bedside[J].Cancer Treat Rev,2014,40(9):1039-1047.
[4]Si W,Shen J,Zheng H,et al.The role and mechanisms of action of micro RNAs in cancer drug resistance[J].Clin Epigenetics,2019,11:25.
[5]Yang Z,Fang S,Di Y,et al.Modulation of NF-κB/mi R-21/PTEN pathway sensitizes non-small cell lung cancer to cisplatin[J].PLo S One,2015,10(3):e0121547.
[6]Vasconcelos M H,Gabriela G M,Guimaraes J E,et al.Targeting mi R-21 induces autophagy and chemosensitivity of leukemia cells[J].Curr Drug Targets,2013,14(10):1135-1143.
[7]Au Yeung C L,Co N N,Tsuruga T,et al.Exosomal transfer of stroma-derived mi R21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1[J].Nat Commun,2016,7:11150-11164.
[8]Akao Y,Noguchi S,Iio A,et al.Dysregulation of micro RNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells[J].Cancer Lett,2011,300(2):197-204.
[9]Wen D,Peng Y,Lin F,et al.Micellar delivery of mi R-34a modulator rubone and paclitaxel in resistant prostate cancer[J].Cancer Res 2017,77(12):3244-3254.
[10]Fan P,Liu L,Yin Y,et al.Micro RNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer[J].Cancer Lett,2016,373(1):130-137.
[11]Iwagami Y,Eguchi H,Nagano H,et al.mi R-320c regulates gemcitabine-resistance in pancreatic cancer via SMARCC1[J].Br J Cancer,2013,109(2):502-511.
[12]Freddie B,Jacques F,Isabelle S,et al.Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2018,68(6):394-424.
[13]Ji Q,Hao X,Zhang M,et al.Micro RNA mi R-34 inhibits human pancreatic cancer tumor-initiating cells[J].PLo S One,2009,4(8):e6816.
[14]Hasegawa S,Eguchi H,Nagano H,et al.Micro RNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer[J].Br J Cancer,2014,111(8):1572-1580.
[15]Le R,Yue Y.The role of mi RNAs in the diagnosis,chemoresistance,and prognosis of pancreatic ductal adenocarcinoma[J].Ther Clin Risk Manag,2018,14:179-187.
[16]Hamada S,Masamune A,Miura S,et al.Mi R-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and proapoptotic regulator BAX[J].Cell Signal,2014,26(2):179-185.
[17]Cao J,Wang Q,Gang W,et al.mi R-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by targeting Wnt5a[J].Int Urol Nephrol,2018,50(10):1811-1819.
[18]Sasaki A,Tsunoda Y,Tsuji M,et al.Decreased mi R-206 expression in BRCA1 wild-type triple-negative breast cancer cells after concomitant treatment with gemcitabine and a Poly(ADP-ribose)polymerase-1 inhibitor[J].Anticancer Res,2014,34(9):4893-4897.
[19]Pan X,Wang R,Wang Z X.The potential role of mi R-451 in cancer diagnosis,prognosis,and therapy[J].Mol Cancer Ther 2013,12(7):1153-1162.
[20]Zhang F,Huang W,Sheng M,et al.Mi R-451 inhibits cell growth and invasion by targeting CXCL16 and is associated with prognosis of osteosarcoma patients[J].Tumor Biol,2015,36(3):2041-2048.
[21]Liu N,Jiang N,Guo R,et al.Mi R-451 inhibits cell growth and invasion by targeting MIF and is associated with survival in nasopharyngeal carcinoma[J].Mol Cancer,2013,12(1):123-131.
[22]Fukumoto I,Kinoshita T,Hanazawa T,et al.Identification of tumour suppressive micro RNA-451a in hypopharyngeal squamous cell carcinoma based on micro R-NA expression signature[J].Br J Cancer,2014,111(2):386-394.
[23]Krakowsky R H E,Wurm A A,Gerloff D,et al.mi R-451a abrogates treatment resistance in FLT3-ITD-positive acute myeloid leukemia[J].Blood Cancer J,2018,8(3):36-40.
[24]Liu Z R,Song Y,Wan L H,et al.Over-expression of mi R-451a can enhance the sensitivity of breast cancer cells to tamoxifen by regulating 14-3-3ζ,estrogen receptorα,and autophagy[J].Life Sci,2016,149:104-113.
[25]Bitarte N,Bandres E,Boni V,et al.Micro RNA-451is involved in the self-renewal,tumorigenicity,and chemoresistance of colorectal cancer stem cells[J].Stem Cells,2011,29(11):1661-1671.
[26]Nan Y,Han L,Zhang A,et al.Mi RNA-451 plays a role as tumor suppressor in human glioma cells[J].Brain Res,2010,1359:14-21.
[27]Chang C,Liu J,He W.A regulatory circuit HP1γ/mi R-451a/c-Myc promotes prostate cancer progression[J].Oncogene,2017,37(4):415-426.