非小细胞肺癌中PTCH1-3’-UTR调控的lncRNAs的ceRNA网络（英文）
|
摘要
目的研究PTCH1-3’-UTR对lnc RNAs表达水平的影响,通过调控网络的分析,提示PTCH1-3’-UTR的功能。方法通过芯片筛选非小细胞肺癌(non-small cell lung cancer,NSCLC)中调控PTCH1-3’-UTR的lnc RNAs,并对部分结果进行荧光定量PCR验证。通过GO和KEGG通路分析调控PTCH1-3’-UTR的lnc RNAs可能的生物学功能。通过TCGA数据分析调控PTCH1-3’-UTR的lnc RNAs与NSCLC患者生存率的直接关系。结果荧光定量PCR验证了PTCH1-3’-UTR上调表达的lnc RNAs(LOC100507547,FAM41C,DOCK4-AS1,AC009305.1,KLF7-IT1,RP11-749H20.1,LINC01511)。GO和KEGG通路分析结果显示,调控PTCH1-3’-UTR的lnc RNAs与一系列的生物过程,包括基因转录、信号转导、蛋白质转运、翻译延伸以及钙信号通路、Jak-STAT信号通路、p53信号通路、胰岛素信号通路有关。TCGA数据分析的结果表明,调控PTCH1-3’-UTR的lnc RNAs中,NSCLC患者中高表达lnc RNA-CDKN2BAS或FAM66D者预后较差,而高表达lnc RNA-LINC00240、LOC400027、ABCC6P2或FLJ10038者可能预示高存活率。结论本研究结果提示了PTCH1-3’-UTR的功能,调控PTCH1-3’-UTR的lnc RNA可作为NSCLC预后标志物。
Objective To investgate the effect of PTCH1-3 '-UTR on the expression of long noncoding RNAs(lnc RNAs) and analyze regulatory networks so as to indicate the function of PTCH1-3 '-UTR. Methods We screened PTCH1-3 '-UTR regulated lnc RNAs in non-small cell lung cancer(NSCLC) by using microarray,and validated the expression by q PCR. To explore the potential mechanisms of these lnc RNAs underlying NSCLC progression,we performed GO and KEGG pathway analysis of the dysregulated lnc RNAs. We also conducted a bioinformatic analysis in TCGA database to identify the association of PTCH1-3 '-UTR regulated lnc RNAs and the overall survival of NSCLC patients. Results The expression of seven PTCH1-3'-UTR up-regulated lnc RNAs(LOC100507547,FAM41 C,DOCK4-AS1,AC009305. 1,KLF7-IT1,RP11-749 H20. 1,LINC01511) were validated by q PCR.The GO and KEGG pathway analysis of the dysregulated lnc RNAs indicated that a series of biological progresses were involved in the function of PTCH1-3'-UTR regulated lnc RNAs,including transcription,signal transduction,protein transport and translational elongation,and several pathways,such as calcium signaling pathway,Jak-STAT signaling pathway,p53 signaling pathway and insulin signaling pathway. Among the lnc RNAs regulating PTCH1-3 '-UTR,6 were shown to be associated with the overall survival of NSCLC patients. High expression of lnc RNA-CDKN2 BAS and FAM66 D related to the probability of lower survival,while high expression of lnc RNA-LINC00240,LOC400027,ABCC6 P2 and FLJ10038 might have a higher probability of survival. Conclusions The study would provide an insight of the function of PTCH1-3 '-UTR,and PTCH1-3'-UTR dysregulated lnc RNAs may be potential prognostic biomarkers for NSCLC.
Objective To investgate the effect of PTCH1-3 '-UTR on the expression of long noncoding RNAs(lnc RNAs) and analyze regulatory networks so as to indicate the function of PTCH1-3 '-UTR. Methods We screened PTCH1-3 '-UTR regulated lnc RNAs in non-small cell lung cancer(NSCLC) by using microarray,and validated the expression by q PCR. To explore the potential mechanisms of these lnc RNAs underlying NSCLC progression,we performed GO and KEGG pathway analysis of the dysregulated lnc RNAs. We also conducted a bioinformatic analysis in TCGA database to identify the association of PTCH1-3 '-UTR regulated lnc RNAs and the overall survival of NSCLC patients. Results The expression of seven PTCH1-3'-UTR up-regulated lnc RNAs(LOC100507547,FAM41 C,DOCK4-AS1,AC009305. 1,KLF7-IT1,RP11-749 H20. 1,LINC01511) were validated by q PCR.The GO and KEGG pathway analysis of the dysregulated lnc RNAs indicated that a series of biological progresses were involved in the function of PTCH1-3'-UTR regulated lnc RNAs,including transcription,signal transduction,protein transport and translational elongation,and several pathways,such as calcium signaling pathway,Jak-STAT signaling pathway,p53 signaling pathway and insulin signaling pathway. Among the lnc RNAs regulating PTCH1-3 '-UTR,6 were shown to be associated with the overall survival of NSCLC patients. High expression of lnc RNA-CDKN2 BAS and FAM66 D related to the probability of lower survival,while high expression of lnc RNA-LINC00240,LOC400027,ABCC6 P2 and FLJ10038 might have a higher probability of survival. Conclusions The study would provide an insight of the function of PTCH1-3 '-UTR,and PTCH1-3'-UTR dysregulated lnc RNAs may be potential prognostic biomarkers for NSCLC.
引文
[1]COHEN M,KICHEVA A,RIBEIRO A,et al.Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms[J].Nat Commun,2015,6:6709.
[2]SHENG T,LI C,ZHANG X,et al.Activation of the hedgehog pathway in advanced prostate cancer[J].Mol Cancer,2004,3:29.
[3]ZHANG X,LIU J,ZANG D,et al.Upregulation of mi R-572transcriptionally suppresses SOCS1 and p21 and contributes to human ovarian cancer progression[J].Oncotarget,2015,6(17):15180-15193.
[4]JOHNSON S M,GROSSHANS H,SHINGARA J,et al.RAS is regulated by the let-7 micro RNA family[J].Cell,2005,120(5):635-647.
[5]WANG Y,LIN G.TP53INP1 3’-UTR functions as a ce RNA in repressing the metastasis of glioma cells by regulating mi RNA activity[J].Biotechnol Lett,2016,38(10):1699-1707.
[6]ZHENG T,CHOU J,ZHANG F,et al.CXCR4 3'UTR functions as a ce RNA in promoting metastasis,proliferation and survival of MCF-7 cells by regulating mi R-146a activity[J].Eur J Cell Biol,2015,94(10):458-469.
[7]HANGAUER MJ,VAUGHN IW,MCMANUS MT.Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs[J].PLo S Genet,2013,9(6):e1003569.
[8]KIM T,CUI R,JEON YJ,et al.MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression[J].Oncotarget,2015,6(22):18780-18789.
[9]GEISLER S,COLLER J.RNA in unexpected places:long non-coding RNA functions in diverse cellular contexts[J].Nat Rev Mol Cell Biol,2013,14(11):699-712.
[10]CHEN S,WU H,LV N,et al.Lnc RNA CCAT2 predicts poor prognosis and regulates growth and metastasis in small cell lung cancer[J].Biomed Pharmacother,2016,82:583-588.
[11]WU Y,LYU H,LIU H,et al.Downregulation of the long noncoding RNA GAS5-AS1 contributes to tumor metastasis in non-small cell lung cancer[J].Sci Rep,2016,6:31093.
[12]LI J,WANG J,CHEN Y,et al.Lnc RNA MALAT1 exerts oncogenic functions in lung adenocarcinoma by targeting mi R-204[J].Am J Cancer Res,2016,6(5):1099-1107.
[13]ZHANG Y,XU Y,FENG L,et al.Comprehensive characterization of lnc RNA-m RNA related ce RNA network across 12 major cancers[J].Oncotarget,2016,7(39):64148-64167.
[14]RUTNAM ZJ,YANG BB.The non-coding 3’UTR of CD44induces metastasis by regulating extracellular matrix functions[J].J Cell Sci,2012,125(Pt 8):2075-2085.
[15]ZHANG Y,XU Y,FENG L,et al.Comprehensive characterization of lnc RNA-m RNA related ce RNA network across 12 major cancers[J].Oncotarget,2016,7(39):64148-64167.
[16]KANG HC,WAKABAYASHI Y,JEN KY,et al.Ptch1overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB)mice[J].J Invest Dermatol,2013,133(5):1311-1320.
[17]LI Y,ZHANG D,CHEN C,et al.Micro RNA-212 displays tumor-promoting properties in non-small cell lung cancer cells and targets the hedgehog pathway receptor PTCH1[J].Mol Biol Cell,2012,23(8):1423-1434.
[18]YOSHIMOTO R,MAYEDA A,YOSHIDA M,et al.MALAT1long non-coding RNA in cancer[J].Biochimica Et Biophysica Acta,2016,1859(1):192-199.
[19]LIN PC,HUANG HD,CHANG CC,et al.Long noncoding RNA TUG1 is downregulated in non-small cell lung cancer and can regulate CELF1 on binding to PRC2[J].BMC Cancer,2016,16:583.
[20]WAN L,SUN M,LIU GJ,et al.Long noncoding RNA PVT1promotes non-small cell lung cancer cell proliferation through epigenetically regulating LATS2 expression[J].Mol Cancer Ther,2016,15(5):1082-1094.
[2]SHENG T,LI C,ZHANG X,et al.Activation of the hedgehog pathway in advanced prostate cancer[J].Mol Cancer,2004,3:29.
[3]ZHANG X,LIU J,ZANG D,et al.Upregulation of mi R-572transcriptionally suppresses SOCS1 and p21 and contributes to human ovarian cancer progression[J].Oncotarget,2015,6(17):15180-15193.
[4]JOHNSON S M,GROSSHANS H,SHINGARA J,et al.RAS is regulated by the let-7 micro RNA family[J].Cell,2005,120(5):635-647.
[5]WANG Y,LIN G.TP53INP1 3’-UTR functions as a ce RNA in repressing the metastasis of glioma cells by regulating mi RNA activity[J].Biotechnol Lett,2016,38(10):1699-1707.
[6]ZHENG T,CHOU J,ZHANG F,et al.CXCR4 3'UTR functions as a ce RNA in promoting metastasis,proliferation and survival of MCF-7 cells by regulating mi R-146a activity[J].Eur J Cell Biol,2015,94(10):458-469.
[7]HANGAUER MJ,VAUGHN IW,MCMANUS MT.Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs[J].PLo S Genet,2013,9(6):e1003569.
[8]KIM T,CUI R,JEON YJ,et al.MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression[J].Oncotarget,2015,6(22):18780-18789.
[9]GEISLER S,COLLER J.RNA in unexpected places:long non-coding RNA functions in diverse cellular contexts[J].Nat Rev Mol Cell Biol,2013,14(11):699-712.
[10]CHEN S,WU H,LV N,et al.Lnc RNA CCAT2 predicts poor prognosis and regulates growth and metastasis in small cell lung cancer[J].Biomed Pharmacother,2016,82:583-588.
[11]WU Y,LYU H,LIU H,et al.Downregulation of the long noncoding RNA GAS5-AS1 contributes to tumor metastasis in non-small cell lung cancer[J].Sci Rep,2016,6:31093.
[12]LI J,WANG J,CHEN Y,et al.Lnc RNA MALAT1 exerts oncogenic functions in lung adenocarcinoma by targeting mi R-204[J].Am J Cancer Res,2016,6(5):1099-1107.
[13]ZHANG Y,XU Y,FENG L,et al.Comprehensive characterization of lnc RNA-m RNA related ce RNA network across 12 major cancers[J].Oncotarget,2016,7(39):64148-64167.
[14]RUTNAM ZJ,YANG BB.The non-coding 3’UTR of CD44induces metastasis by regulating extracellular matrix functions[J].J Cell Sci,2012,125(Pt 8):2075-2085.
[15]ZHANG Y,XU Y,FENG L,et al.Comprehensive characterization of lnc RNA-m RNA related ce RNA network across 12 major cancers[J].Oncotarget,2016,7(39):64148-64167.
[16]KANG HC,WAKABAYASHI Y,JEN KY,et al.Ptch1overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB)mice[J].J Invest Dermatol,2013,133(5):1311-1320.
[17]LI Y,ZHANG D,CHEN C,et al.Micro RNA-212 displays tumor-promoting properties in non-small cell lung cancer cells and targets the hedgehog pathway receptor PTCH1[J].Mol Biol Cell,2012,23(8):1423-1434.
[18]YOSHIMOTO R,MAYEDA A,YOSHIDA M,et al.MALAT1long non-coding RNA in cancer[J].Biochimica Et Biophysica Acta,2016,1859(1):192-199.
[19]LIN PC,HUANG HD,CHANG CC,et al.Long noncoding RNA TUG1 is downregulated in non-small cell lung cancer and can regulate CELF1 on binding to PRC2[J].BMC Cancer,2016,16:583.
[20]WAN L,SUN M,LIU GJ,et al.Long noncoding RNA PVT1promotes non-small cell lung cancer cell proliferation through epigenetically regulating LATS2 expression[J].Mol Cancer Ther,2016,15(5):1082-1094.