差异表达miRNA在胰腺癌预后判断中的价值

doi:10.3969/j.issn.1004-616x.2019.03.001

摘要/Abstract

摘要： 目的：分析胰腺癌组织和正常组织差异表达的miRNA，筛选与胰腺癌预后相关的生物标志。方法：下载并整理基因芯片表达汇编数据库（GEO）中GSE32678和GSE71533芯片数据集原始数据，应用R语言筛选差异表达miRNA，结合GSE24279数据集，获得差异表达的miRNA并取交集。应用生物信息学分析工具对交集miRNA进行靶基因预测，进而对靶基因进行功能分析，构建蛋白互作网络（PPI）、miRNA-mRNA调控网络、miRNA-mRNA-pathway调控网络，结合肿瘤基因组图谱数据库（TCGA）中胰腺癌样本的miRNA表达及预后数据，筛选出胰腺癌预后相关标志物。结果：共筛选出胰腺癌组织和正常组织22个交集miRNA，其中hsa-miR-30a-5p、hsa-miR-551a、hsa-miR-375与胰腺癌患者的生存预后密切相关。hsa-miR-125b-5p、hsa-miR-221-3p、hsamiR-31-5p、hsa-miR-222-3p、hsa-miR-10a-5p是miRNA-mRNA调控网络中的核心miRNA。结论：通过对GEO和TCGA数据库胰腺癌相关数据的分析发现hsa-miR-30a-5p、hsa-miR-551a、hsa-miR-375显著影响胰腺癌患者的预后，可以作为判断预后的标志。

关键词: 胰腺癌, miRNA, 预后, 基因芯片表达汇编数据库, 肿瘤基因组图谱数据库

Abstract: OBJECTIVE:To analyze associations between differentially expressed miRNAs and development of pancreatic cancers, and to screen biomarkers which might be related to prognosis of pancreatic cancers. METHODS:Data of GSE32678 and GSE71533 datasets in Gene Expression Omnibus (GEO) were downloaded to screen differentially expressed miRNAs by using R language and the intersection of the three data sets were taken. Bioinformatics analysis tool was used to predict target genes of overlapping miRNAs, to perform functional analysis on the target genes,and to construct a protein interaction network (PPI),a miRNA-mRNA network,and a miRNA-mRNA-pathway network. The markers which were related to prognosis of pancreatic cancers were screened by using the expression and prognosis data of miRNAs of pancreatic cancer samples in the Cancer Genome Atlas (TCGA). RESULTS:A total of 22 overlapping miRNAs were screened,and hsamiR-30a-5p,hsa-miR-551a,and hsa-miR-375 were closely related to the prognosis of pancreatic cancer. The core miRNAs in the miRNA-mRNA network were hsa-miR-125b-5p,hsa-miR-221-3p,hsa-miR-31-5p, hsa-miR-222-3p and hsa-miR-10a-5p. CONCLUSION:Analysis of data of pancreatic cancers in the GEO and TCGA databases reveal that hsa-miR-30a-5p,hsa-miR-551a,and hsa-miR-375 significantly affected the prognosis of pancreatic cancers and could be used as markers for prognosis.

Key words: pancreatic cancer, miRNA, prognosis, GEO database, TCGA database

中图分类号:

R318.04

高杰, 张晓, 魏超. 差异表达miRNA在胰腺癌预后判断中的价值[J]. 癌变·畸变·突变, 2019, 31(3): 173-179.

GAO Jie, ZHANG Xiao, WEI Chao. Involvement of differentially expressed miRNA in prognosis of pancreatic cancers[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2019, 31(3): 173-179.

参考文献

[1] CHEN W, ZHENG R, ZHANG S, et al. Report of incidence and mortality in China cancer registries, 2009[J]. Chin J Cancer Res,2013,25(1):10-21.
[2] TORRE L A,FREDDIE B,SIEGEL R L,et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2):69-90.
[3] YANG W, HUA Z, GAO X, et al. Identification of a three-miRNA signature as a blood-borne diagnostic marker for early diagnosis of lung adenocarcinoma[J]. Oncotarget,2016,7(18):26070-26086.
[4] SONJA G, TIBOR S, HELMUT F, et al. Preoperative/neoadjuvant therapy in pancreatic cancer:a systematic review and meta-analysis of response and resection percentages[J]. PLoS Med,2010,7(4):e1000267.
[5] 魏超,张晓,高杰. 长链非编码RNA与mRNA在胰腺癌中的差异表达及其预后价值[J]. 癌变·畸变·突变,2019, 31(2):119-126.
[6] RAHELEH A,ULF S,MICHAEL L,et al. MicroRNAmRNA interactions in colorectal cancer and their role in tumor progression[J]. Genes Chromosomes Cancer, 2015, 54(3):129-141.
[7] WENBIN Y,QING L,CHUNG-KWUN AMY W,et al. The effect of central loops in miRNA:MRE duplexes on the efficiency of miRNA-mediated gene regulation[J]. PLoS One,2008,3(3):e1719.
[8] SCHETTER A J, SUET YI L, SOHN J J, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma[J]. JAMA,2008,299(4):425.
[9] YANG S, SUI J, LIANG G. Diagnosis value of aberrantly expressed microRNA profiles in lung squamous cell carcinoma:a study based on the Cancer Genome Atlas[J]. Peer J,2017,5(2):e4101.
[10] YOSHITO T, HIDETOSHI E, HIROAKI N, et al. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma[J]. Sichuan Med J,2012,56(1):167-175.
[11] UEDA T, VOLINIA S, OKUMURA H, et al. Relation between microRNA expression and progression and prognosis of gastric cancer:a microRNA expression analysis[J]. Lancet Oncol,2010,11(2):136-146.
[12] DONAHUE T R, TRAN L M, HILL R, et al. Integrative survival-based molecular profiling of human pancreatic cancer[J]. Clin Cancer Res,2012,18(5):1310-1352.
[13] BAUER A S, KELLER A, COSTELLO E, et al. Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue[J]. PLoS One,2012,7(4):e34151.
[14] WEI H D, SHERMAN B T, QINA T, et al. DAVID bioinformatics resources:expanded annotation database and novel algorithms to better extract biology from large gene lists[J]. Nucleic Acids Res,2007,35(2):W169-W175.
[15] SZKLARCZYK D, MORRIS J H, COOK H, et al. The STRING database in 2017:quality-controlled proteinprotein association networks, made broadly accessible[J]. Nucleic Acids Res,2017,45:D362-D368.
[16] SHANNON P, MARKIEL A, OZIER O, et al. Cytoscape:a software environment for integrated models of biomolecular interaction networks[J]. Genome Res, 2003,13(11):2498-2504.
[17] 魏巧. 食管鳞癌miRNA与全基因组表达谱及其调控网络的研究[D]. 上海:复旦大学,2013.
[18] VINCENT A, HERMAN J, SCHULICK R, et al. Pancreatic cancer[J]. Lancet,2011,378(9791):607-620.
[19] CHEN W, ZHENG R, BAADE P D, et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115-132.
[20] YANG G Y, WAGNER T D, FUSS M, et al. Multimodality approaches for pancreatic cancer[J]. CA Cancer J Clin,2010,55(6):352-367.
[21] RABOFSKI J L, VASHIST Y K, KALININA T, et al. HSP90 als Therapie-Target bei Gemcitabine und 5-Fluorouracil resistentem Pankreaskarzinom[M]. Heidelberg:Springer Berlin Heidelberg,2010:67-68.
[22] YONG S L, DUTTA A. MicroRNAs in cancer[J]. Annu Rev Pathol Mech Dis,2009,4(4):199-227.
[23] YUAN W, TANG W, XIE Y, et al. New combined microRNA and protein plasmatic biomarker panel for pancreatic cancer[J]. Oncotarget, 2016, 7(48):80033-80045.
[24] ZHANG Z,PAN B,LV S,et al. Integrating microRNA expression profiling studies to systematically evaluate the diagnostic value of microRNAs in pancreatic cancer and validate their prognostic significance with the Cancer Genome Atlas Data[J]. Cell Physiol Biochem, 2018, 49(2):678-695.
[25] DOU D, YANG S, LIN Y, et al. An eight-miRNA signature expression-based risk scoring system for prediction of survival in pancreatic adenocarcinoma[J]. Cancer Biomark,2018,23(1):79-93.
[26] LI C H, XIAO Z, HUNG-MAN T J, et al. EZH2 coupled with HOTAIR to silence microRNA-34a by the induction of heterochromatin formation in human pancreatic ductal adenocarcinoma[J]. Int J Cancer, 2016, 140(1):120-129.
[27] TURASHVILI G,LIGHTBODY E D,TYRYSHKIN K,et al. Novel prognostic and predictive microRNA targets for triple-negative breast cancer[J]. FASEB J,2018,32(11):201800120R.
[28] YANG D, YAN R, XIN Z, et al. Deregulation of microRNA-375 inhibits cancer proliferation migration and chemosensitivity in pancreatic cancer through the association of HOXB3[J]. Am J Transl Res,2016,8(3):1551-1559.
[29] ZHOU J, SONG S, CEN J, et al. MicroRNA-375 is downregulated in pancreatic cancer and inhibits cell proliferation in vitro[J]. Oncol Res,2012,20(5/6):197.
[30] TAO J, CONG H, WANG H, et al. MiR-30a-5p inhibits osteosarcoma cell proliferation and migration by targeting FOXD1[J]. Biochem Biophys Res Commun, 2018,503(2):1092-1097.
[31] WANG Y,QIU C,LU N,et al. FOXD1 is targeted by miR-30a-5p and miR-200a-5p and suppresses the proliferation of human ovarian carcinoma cells by promoting p21 expression in a p53-independent manner[J]. Int J Oncol,2018,52(6):2130-2142.
[32] LI Z, CAO Y, JIE Z, et al. miR-495 and miR-551a inhibit the migration and invasion of human gastric cancer cells by directly interacting with PRL-3[J]. Cancer Lett, 2012,323(1):41-47.
[33] 吴孟闱. miR-125b-5p参与胰腺癌侵袭转移分子机制的研究[D]. 沈阳:中国医科大学,2018.
[34] ZHOU C, MA J, HUANG L, et al. Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1[J]. Oncogene,2019,38(8):1256-1268.
[35] PENG H,WANG L,SU Q,et al. MiR-31-5p promotes the cell growth, migration and invasion of colorectal cancer cells by targeting NUMB[J]. Biomed Pharmacother, 2019,109:208-216.
[36] CHANG Y, WENG S, YANG S, et al. A ThreemicroRNA signature as a potential biomarker for the early detection of oral cancer[J]. Int J Mol Sci, 2018, 19(3):758-775.
[37] XIONG G, HUANG H, FENG M, et al. MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma[J]. Exp Clin Cancer Res, 2018,37(1):76-91.
[38] RAVI R K,WEBER E,MCMAHON M,et al. Activated Raf-1 causes growth arrest in human small cell lung cancer cells[J]. J Clin Invest,1998(1):153-159.
[39] DAVIS R J. Signal transduction by the JNK group of MAP kinases[J]. Cell,2000,103(2):239-252.
[40] POTENTE M, URBICH C, SASAKI K, et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization[J]. J Clin Invest, 2005, 115(9):2382-2392.
[41] BOISSIER P, HUYNH-DO U. The guanine nucleotide exchange factor Tiam1:A Janus-faced molecule in cellular signaling[J]. Cell Signal,2014,26(3):483-491.
[42] HOCKENBERY D M, ZUTTER M, HICKEY W, et al. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death[J]. Proc Natl Acad Sci USA,1991,88(16):6961-6965.