Abstract
Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.
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References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
Crawford ED, Higano CS, Shore ND, Hussain M, Petrylak DP. Treating patients with metastatic castration-resistant prostate cancer: a comprehensive review of available therapies. J Urol 2015.
Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24(18):1967–2000.
Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ. Biological functions of microRNAs: a review. J Physiol Biochem. 2011;67(1):129–39.
Fang YX, Gao WQ. Roles of microRNAs during prostatic tumorigenesis and tumor progression. Oncogene. 2014;33(2):135–47.
Boll K, Reiche K, Kasack K, Morbt N, Kretzschmar AK, Tomm JM, Verhaegh G, Schalken J, von Bergen M, Horn F, Hackermuller J. MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene. 2013;32(3):277–85.
Kojima S, Enokida H, Yoshino H, Itesako T, Chiyomaru T, Kinoshita T, Fuse M, Nishikawa R, Goto Y, Naya Y, Nakagawa M, Seki N. The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer. J Hum Genet. 2014;59(2):78–87.
Xu B, Wang N, Wang X, Tong N, Shao N, Tao J, Li P, Niu X, Feng N, Zhang L, Hua L, Wang Z, Chen M. MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer. Prostate. 2012;72(11):1171–8.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22.
Kroiss A, Vincent S, Decaussin-Petrucci M, Meugnier E, Viallet J, Ruffion A, Chalmel F, Samarut J, Allioli N. Androgen-regulated microRNA-135a decreases prostate cancer cell migration and invasion through downregulating ROCK1 and ROCK2. Oncogene. 2015;34(22):2846–55.
Setlur SR, Royce TE, Sboner A, Mosquera JM, Demichelis F, Hofer MD, Mertz KD, Gerstein M, Rubin MA. Integrative microarray analysis of pathways dysregulated in metastatic prostate cancer. Cancer Res. 2007;67(21):10296–303.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
Nakabayashi M, Hayes J, Taplin ME, Lefebvre P, Lafeuille MH, Pomerantz M, Sweeney C, Duh MS, Kantoff PW. Clinical predictors of survival in men with castration-resistant prostate cancer: evidence that Gleason score 6 cancer can evolve to lethal disease. Cancer. 2013;119(16):2990–8.
Hendriks LE, Smit EF, Vosse BA, Mellema WW, Heideman DA, Bootsma GP, Westenend M, Pitz C, de Vries GJ, Houben R, Grunberg K, Bendek M, Speel EJ, Dingemans AM. EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases? Lung Cancer. 2014;84(1):86–91.
Nickerson NK, Mohammad KS, Gilmore JL, Crismore E, Bruzzaniti A, Guise TA, Foley J. Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad. PLoS One. 2012;7(1):e30255.
Chang YS, Chen WY, Yin JJ, Sheppard-Tillman H, Huang J, Liu YN. EGF Receptor promotes prostate cancer bone metastasis by downregulating miR-1 and activating TWIST1. Cancer Res 2015.
Siu MK, Abou-Kheir W, Yin JJ, Chang YS, Barrett B, Suau F, Casey O, Chen WY, Fang L, Hynes P, Hsieh YY, Liu YN, Huang J, Kelly K. Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance. Oncotarget. 2014;5(11):3770–84.
Yang X, Yang K, Kuang K. The efficacy and safety of EGFR inhibitor monotherapy in non-small cell lung cancer: a systematic review. Curr Oncol Rep. 2014;16(6):390.
Ojemuyiwa MA, Madan RA, Dahut WL. Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development. Expert Opin Emerg Drugs. 2014;19(4):459–70.
Chen Q, Quan Q, Ding L, Hong X, Zhou N, Liang Y, Wu H. Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors. Oncotarget 2015.
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This study was supported by the National Natural Science Foundation of China (nos. 81202034 and 81370849), the Natural Science Foundation of Jiangsu Province (BK2012336 and BL2013032), Nanjing City (201201053), Southeast University (3290002402), and the Science Foundation of Ministry of Education of China (20120092120071).
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Bin Xu, Tao Tao, Yiduo Wang, and Fang Fang contributed equally to this work.
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Supplementary Figure 1
MiR-135a potentially targets multiple oncogenic pathways. A. miR-135a potentially targets multiple components of each indicated oncogenic pathway as predicted by microRNA.org. Shown are the gene names, number of potential binding sites, gene expression changes in cells overexpressing miR-135a (data retrieved form GSE45620), and the affected pathways. (GIF 41 kb)
Fig7
B. Schematic representation of the binding site of miR-135a to target transcripts as predicted by microRNA.org. (GIF 80 kb)
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Xu, B., Tao, T., Wang, Y. et al. hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR. Tumor Biol. 37, 14141–14151 (2016). https://doi.org/10.1007/s13277-016-5196-6
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DOI: https://doi.org/10.1007/s13277-016-5196-6