张世超,欧阳燕,兰应武,唐福州,胡祖权,曾柱
ZHANG Shichao,OUYANG Yan,LAN Yingwu,TANG Fuzhou,HU Zuquan,ZENG Zhu

• 1:贵州医科大学生物与工程学院
• 2:贵州医科大学基础医学院

摘要(Abstract)：

目的:探讨可变剪接在肺腺癌预后中的作用。方法:在TCGA数据库中收集474例肺腺癌组织的RNA-seq数据,绘制可变剪接图谱;通过单因素Cox回归分析确定肺腺癌中存活相关的剪接事件,再利用最小绝对收缩模型筛选用于监测存活的预后因子;收集5例肺腺癌患者的癌组织,采用PCR扩增及琼脂糖凝胶电泳检测CHEK1、KIF23、MCM7和FN1的mRNA亚型条带。结果:在肺腺癌中存在着大量的可变剪接事件并与预后相关,包括CHEK1、KIF23、MCM7和FN1,通过生物信息学利用可变剪接事件构建了高效的风险预测模型;KEGG途径分析表明,主要富集的基因与""regulation of autophagy"、"central carbon metabolism in cancer"和"cell cycle"有关;5例肺腺癌患者的癌组织PCR扩增结果显示,可变剪接核心基因CHEK1、KIF23、FN1确实存在CHEK1-AP-19309、KIF23-AP-31390、FN1-ES-57398等剪接体。结论:可变剪接事件可作为预测肺腺癌患者临床结果的指标,可为肺腺癌患者制定个体化治疗方案提供依据。
Objective: To explore the relationship between alternative splicing and prognosis of lung adenocarcinoma. Methods: Integrative analysis of RNA sequencing and clinical information were utilized to identify survival associated splicing events in lung adenocarcinoma. Then, several prognosis-related splicing events were submitted to develop moderate predictors for survival monitoring by using least absolute shrinkage and selection operator model. Results: There are a large number of alternative splicing events in lung adenocarcinoma, which are related to prognosis,including CHEK1, KIF23, MCM7 and FN1. We constructed an efficient risk prediction model using alternative splicing events. KEGG pathway analysis showed that the major enriched genes were "regulation of autophagy", "carbon metabolism in cancer" and "cell cycle". Conclusion: Alternative splicing events could be used as a prognostic indicator for predicting the clinical outcomes of patients with lung adenocarcinoma, providing individualized treatments with important clinical significance for patients with lung adenocarcinoma.

关键词(KeyWords)： 肺肿瘤;预后;肺腺癌;可变剪接;临床结果;核心基因
lung neoplasms;prognosis;lung adenocarcinoma;alternative splicing;clinical outcome;core genes

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(31771014,11762006,31660258);; 贵州省科技计划项目(2019-1275,2019-2787);; 贵州医科大学博士启动基金(YJ2017-10)

作者(Author): 张世超,欧阳燕,兰应武,唐福州,胡祖权,曾柱
ZHANG Shichao,OUYANG Yan,LAN Yingwu,TANG Fuzhou,HU Zuquan,ZENG Zhu

DOI: 10.19367/j.cnki.1000-2707.2019.11.003

参考文献(References)：

• [1] GRIFFITH M,GRIFFITH O L,MWENIFUMBOM J,et al.Alternative expression analysis by RNA sequencing [J].Nature Methods,2010,7(10):843-847.
• [2] LU M,ZHAN X.The crucial role of multiomic approach in cancer research and clinically relevant outcomes [J].The EPMA Journal,2017,9(1):77-102.
• [3] áNGELES A,CONESA A.Single-cell RNAseq for the study of isoforms-how is that possible[J].Genome Biology,2016,19(1):110-115.
• [4] 从美丽,周蓓,吕晓敏,等.大鼠酒精性肝损伤模型RNA可变剪接变化分析[J].热带医学杂志,2018,18(8):41-44.
• [5] LI Y,SUN N,LU Z,et al.Prognostic alternative mRNA splicing signature in non-small cell lung cancer [J].Cancer Letters,2017,393:40-51.
• [6] CHEN J,HU L,ZHANG F,et al.Downregulation of carbonic anhydrase IV contributes to promotion of cell proliferation and is associated with poor prognosis in non-small cell lung cancer [J].Oncology Letters,2017,14(4):5046-5050.
• [7] WABG E T,SANDBERG R ,LUO S,et al.Alternative isoform regulation in human tissue transcriptomes [J].Nature,2008,456(7221):470-476.
• [8] ZHENG Z,WEI X,HILDEBRANDT A,et al.A computational method for studying the relation between alternative splicing and DNA methylation [J].Nucleic Acids Research,2016,44(2):19-19.
• [9] TOMCZAK K,CZERWISKA P,WIZNEROWICZ M.The cancer genome atlas (TCGA):an immeasurable source of knowledge [J].Contemporary Oncology,2015,19(1A):68-77.
• [10]WU Z,PENG Z,HE R,et al.Prognostic index of aberrant mRNA splicing profiling acts as a predictive indicator for hepatocellular carcinoma based on TCGA SpliceSeq data [J].International Journal of Oncology,2019,55(2):425-438.
• [11]LIN P,HE R,HUANG Z,et al.Role of global aberrant alternative splicing events in papillary thyroid cancer prognosis [J].Aging,2017,11(7):2082-2097.
• [12]YU X,ZHANG Y,MA X,et al.miR-195 Potentiates the efficacy of Microtubule-targeting agents in Non-small cell lung cancer [J].Cancer Letters,2018,427(28):85-93.
• [13]VIKBERG A L,VOODER T,LOKK K,et al.Mutation analysis and copy number alterations of KIF23 in non-small-cell lung cancer exhibiting KIF23 over-expression [J].Onco Targets and Therapy,2017,10:4969-4979.
• [14]LIU Y Z,WANG B S,JIANG Y Y,et al.MCMs expression in lung cancer:implication of prognostic significance [J].Journal of Cancer,2017,8(18):3641-3647.
• [15]HARAO M,MITTENDORF E A,RADVANYI L G.Peptide-based vaccination and induction of CD8+ T-cell responses against tumor antigens in breast cancer [J].Biodrugs,2015,29(1):15-30.
• [16]NIU Y,FENG M,HUANG W,et al.Long non-coding RNA TUG1 is involved in cell growth and chemoresistance of small cell lung cancer by regulating LIMK2b via EZH2 [J].Molecular Cancer,2017,16(1):5-10.
• [17]SUC C,HRYDZIUSZKO O,LEE D,et al.Integration of somatic mutation,expression and functional data reveals potential driver genes predictive of breast cancer survival [J].Bioinformatics,2015,31(16):2607-2613.
• [18]MC R,CLELAND J,KIM R,et al.SpliceSeq:a resource for analysis and visualization of RNA-Seq data on alternative splicing and its functional impacts [J].Bioinformatics,2012,28:2385-2387.
• [19]SOAVE D M,STRUG L J.Testing calibration of cox survival models at extremes of event risk [J].Frontiers in Genetics,2018,9:177-182.
• [20]FU Y T,ZHANG D Q,ZHOU L,et al.Has-MiR-196a-2 is up-regulated and acts as an independent unfavorable prognostic factor in thyroid carcinoma [J].European Review for Medical & Pharmacological Sciences,2018,22(9):2707-2712.
• [21]QIU X,MAO Q,TANG Y,et al.Reversed graph embedding resolves complex single-cell trajectories [J].Nature Methods,2017,14(10):979-982.
• [22]NEELAMRAJU Y,GONZALEZ P A,BHAT N P,et al.Mutational landscape of RNA-binding proteins in human cancers [J].RNA Biology,2018,15(1):115-129.
• [23]KAMTCHUENG C,STEBENNE M,DELANNOY A,et al.Alternative splicing of TAF6:downstream transcriptome impacts and upstream RNA splice control elements [J] Plos One,2014,9(7):e102399.
• [24]CHANG L,FANG S,CHEN Y,et al.Inhibition of FASN suppresses the malignant biological behavior of non-small cell lung cancer cells via deregulating glucose metabolism and AKT/ERK pathway [J].Lipids in Health and Disease,2019,18(1):118-123.
• [25]GUO W,FRENTEET P S.Alternative CD44 splicing in intestinal stem cells and tumorigenesis [J].Oncogene,2014,33:537-538.
• [26]MIGUEL F D,PAJARES M J,MARTINEZ-TERROBA E,et al.A large-scale analysis of alternative splicing reveals a key role of QKI in lung cancer [J].Molecular Oncology,2016,10(9):1437-1449.
• [27]PAIK P K,DRILIN A,FAN P D,et al.Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping [J].Cancer Discovery,2015,5(8):842-849.
• [28]ZHU D Y,LI X N,QI Y,et al.MiR-454 promotes the progression of human non-small cell lung cancer and directly targets PTEN [J].Biomedicine & Pharmacotherapy,2016,81:79-85.
• [29]MENG L,XU Y,XU C,et al.Biomarker discovery to improve prediction of breast cancer survival:using gene expression profiling,meta-analysis,and tissue validation [J].Oncotargets & Therapy,2016,9:6177-6185.
• [30]MARTINEZ-MONTIEL N,ROSAS-MURRITEA N H,MARTINEZ-MONTIEL M,et al.Microbial and natural metabolites that inhibit splicing:a powerful alternative for cancer treatment[J].Biomed Research International,2016,2016(23):1-14.

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