Hsa-miR-125b在人胃癌耐药细胞株中的表达及其靶基因的功能分析
收稿日期: 2013-07-17
修回日期: 2013-10-31
网络出版日期: 2014-01-25
基金资助
国家自然科学基金项目(编号：81272454，81071701)和西北民族大学中央高校基本科研业务费专项资金项目(编号：ZYZ2011105)资助
Expression profiling and functional analysis of hsa-miR-125b and its target genes in drug-resistant cell line of human gastric cancer
Received date: 2013-07-17
Revised date: 2013-10-31
Online published: 2014-01-25
研究表明, Hsa-miR-125b在人胃癌耐氟尿嘧啶细胞株BGC823/Fu中表达下降。为进一步探讨hsa-miR-125b在获得性耐药中所起的作用, 文章应用miRbase、靶基因预测软件、Gene Ontology数据库及KEGG数据库对hsa-miR-125b的序列特征、进化保守性、靶基因及功能以及靶基因所参与的信号通路等进行了深入的生物信息学分析。结果显示：has-miR-125b在多个物种之间具有高度序列保守性; 通过软件预测获得hsa-miR- 125b 靶基因79个, 其分子功能包括转录调节、蛋白质结合和肽酶类活性等(P<0.001), 其所参与的生物学过程主要有细胞周期、细胞增殖、细胞凋亡的正性或负性调控以及细胞因子刺激反应性、药物反应性、DNA损伤反应性等(P<0.001), 调控包括MAPK、Wnt、p53等多条信号转导通路(P<0.01)。上述结果表明hsa-miR-125b可能参与调控多个生物学过程和信号转导通路, 而其中细胞增殖、细胞凋亡、细胞周期等生物学过程以及MAPK、Wnt、p53等信号通路已被证实与肿瘤耐药的发生有关。因此, hsa-miR-125b可能通过调控上述环节中的靶基因来影响肿瘤细胞对药物的敏感性, 从而为hsa-miR-125b在肿瘤耐药中的作用机制提供新的研究线索。
关键词： hsa-miR-125b; 生物信息学; 靶基因; 肿瘤化疗耐药; 胃癌
程燕, 陈琳, 曹忻, 哈斯其美格, 谢小冬 . Hsa-miR-125b在人胃癌耐药细胞株中的表达及其靶基因的功能分析[J]. 遗传, 2014 , 36(2) : 119 -126 . DOI: 10.3724/SP.J.1005.2014.0119
The expression of hsa-miR-125b is significantly downregulated in the fluorouracil-resistant cell line of human gastric cancer (BGC823/Fu). In order to investigate the role of hsa-miR-125b in the drug-resistance acquisition process of human gastric cancer, we performed a series of analysis on the sequence characteristics, species conservation, target genes, function annotation and signal transduction pathway enrichment of hsa-miR-125b using a combined bioinformatic approach such as miRbase, TargetScan6.2, PicTar, miRanda, Gene Ontology(GO) and KEGG. The results showed that the sequence of miR-125b is highly conserved in multiple species. A total of 79 target genes related to transcription regulation, protein binding, enzyme activity (P<0.001) were predicted by bioinformatics software. These genes involved in many biological processes including cell cycle, cell proliferation, cell apoptosis and cell responses to cytokine, drug responses and DNA damage (P<0.001). And these target genes mainly belong to MAPK, Wnt and p53 signal transduction pathways (P<0.01). The results revealed that hsa-miR-125b may regulate multiple biological processes and signal transduction pathways, and drug-resistant occurrence is associated with cell proliferation, cell apoptosis, cell cycle and signaling pathways including MAPK, Wnt and p53. We suggest that hsa-miR-125b may affect chemosensitivity by regulating target genes involved in the above processes and these target genes might be reliable candidates for exploring the role of hsa-miR-125b in tumor chemoresistance.
[1] Lippert TH, Ruoff HJ, Volm M. Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure. Arzneimittelforschung, 2008, 58(6): 261–264. <\p>
[2] O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. C-Myc-regulated microRNAs modulate E2F1 expres-sion. Nature, 2005, 435(7043): 839–843. <\p>
[3] Blower PE, Chung JH, Verducci JS, Lin S, Park JK, Dai Z, Liu CG, Schmittgen TD, Reinhold WC, Croce CM, Weinstein JN, Sadee W. MiRNAs modulate the chemosen-sitivity of tumor cells. Mol Cancer Ther, 2008, 7(1): 1–9. <\p>
[4] Zheng T, Wang J, Chen X, Liu L. Role of microRNA in anti-cancer drug resistance. Int J Cancer, 2010, 126(1): 2–10. <\p>
[5] Iorio MV, Croce CM. MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol, 2009, 27(34): 5848–5856. <\p>
[6] Kozomara A, Griffiths-Jones S. miRBase: integrating mi-croRNA annotation and deep-sequencing data. Nucleic Acids Res, 2011, 39: 152–157. <\p>
[7] Lewis B P, Burge C B, Bartel V. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are MicroRNA targets. Cell, 2005, 120(1): 15–20. <\p>
[8] Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA. org resource: targets and expression. Nucleic Acids Res, 2008, 36: 149–153. <\p>
[9] Hsu SD, Lin FM, Wu WY, Liang C, Huang WC, Chan WL, Tsai WT, Chen GZ, Lee CJ, Chiu CM, Chien CH, Wu MC, Huang CY, Tsou AP, Huang HD. miRTarBase: a database curates experimentally validated microRNA-target inter-actions. Nucleic Acids Research, 2011, 39: 163–169. <\p>
[10] Fojo T. Multiple paths to a drug resistance phenotype: mutations, translocations, deletions and amplification of coding genes or promoterregions, epigenetic changes and microRNAs. Drug Resist Updat, 2007, 10(1–2): 59–67. <\p>
[11] Sun YM, Lin KY, Chen YQ. Diverse functions of miR-125 family in differentcell contexts. J Hematol Oncol, 2013, 6: 6. <\p>
[12] Xia HF, He TZ, Liu CM, Cui Y, Song PP, Jin XH, Ma X. MiR-125b expression affects the proliferation and apop-tosis of human glioma cells by targeting Bmf. Cell Physiol Biochem, 2009, 23(4–6): 347–358. <\p>
[13] Mizuno Y, Yagi K, Tokuzawa Y, Kanesaki-Yatsuka Y, Suda T, Katagiri T, Fukuda T, Maruyama M, Okuda A, Amemiya T, Kondoh Y, Tashiro H, Okazaki Y. miR- 125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun, 2008, 368(2): 267–272. <\p>
[14] 胡斌, 吴爱国, 李学孝, 纪术峰, 王梦川, 吴凯, 邵国利. miR-125b-1 增强乳腺癌SKBR-3 细胞对紫杉醇的药物敏感性. 热带医学杂志, 2012, 12(7): 789–792. <\p>
[15] 智慧, 朱伟, 王同杉, 王建, 束永前, 刘平. miR-125b靶向抑制BCL2、MCL1表达对胃癌SGC7901/VCR细胞多药耐药性的影响. 南京医科大学学报, 2011, 6: 777–781. <\p>
[16] Kong F, Sun C, Wang Z, Han L, Weng D, Lu Y, Chen G. miR-125b confers resistance of ovarian cancer cells to cisplatin by targeting pro-apoptotic Bcl-2 antagonist killer 1(BAK1)expression. J Huazhong Univ Sci Technolog Med Sci, 2011, 31(4): 543–549. <\p>
[17] Shi L, Zhang J, Pan T, Zhou J, Gong W, Liu N, Fu Z, You Y. MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation. Brain Res, 2010, 1312: 120–126. <\p>
[18] Duman BB, Sahin B, Acikalin A, Ergin M, Zorludemir S. PTEN, Akt, MAPK, p53 and p95 expression to predict trastuzumab resistance in HER2 positive breast cancer. J BUON, 2013, 18(1): 44–50. <\p>
[19] Pritchard AL, Hayward NK. Molecular pathways: mito-gen-activated protein kinase pathway mutations and drug resistance. Clin Cancer Res, 2013, 19(9): 2301– 2309. <\p>
[20] Paunovic V, Harnett MM. Mitogen-activated protein kinases as therapeutic targets for rheumatoid arthritis. Drugs, 2013, 73(2): 101–115.
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