Identification of a novel microRNA-mRNA regulatory biomodule in human prostate cancer.

Abstract

Our recent study identified a list of differentially expressed microRNAs (miRNAs) in human prostate cancer (PCa) tissues compared to adjacent benign prostate tissues. In the current study, to identify the crucial miRNA-mRNA regulatory biomodule involved into prostate carcinogenesis based on the previous miRNA expression profile in PCa, we proposed an integrated systematic approach which combined miRNA-mediated gene expression regulatory network analysis, experimental validations in vitro and in vivo, as well as clinical significance evaluation. As a result, the CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I axis was identified as a bottleneck in the miRNA-mediated gene expression regulatory network of PCa according to network topological analysis. The direct binding relationship between TP73 and PCa downregulated miR-193a-5p, and the direct binding relationship between UBE2I and PCa upregulated miR-188-5p were both experimentally validated. In addition, miR-193a-5p had a more significant regulatory effect on the tumor promoter isoform of TP73-deltaNp73 than on the tumor suppressive isoform of TP73-TAp73. Importantly, the deregulation of either the miR-193a-5p-TP73 or miR-188-5p-UBE2I axes was significantly associated with aggressive progression and poor prognosis in PCa patients. Gain- and loss-of-function experiments showed that miR-193a-5p efficiently inhibited in vitro PCa cell proliferation, migration, and invasion, and in vivo tumor growth, and markedly induced PCa cell apoptosis via regulating TP73 with a corresponding suppression of the CCND1-RNASEL-CDKN1A-MDM2 axis. In contrast, miR-188-5p exerted its tumor promoter roles through targeting UBE2I with a subsequent activation of the CCND1-RNASEL-CDKN1A-MDM2 axis. Taken together, this integrated analysis revealed the potential roles of the miR-193a-5p/TP73 and miR-188-5p/UBE2i negative regulation pairs in PCa. In addition to the significant clinical relevance, miR-193a-5p- and miR-188-5p-regulated CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I signaling may be a novel regulatory biomodule in prostate carcinogenesis.

• Authors: Yanqiong Zhang, Funeng Jiang, Huichan He, Jianheng Ye, Xia Mao, Qiuyan Guo, Shu-Lin Wu, Weide Zhong, Chin-Lee Wu, Na Lin
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 3 Pg. 301 (02 21 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29467540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN188 microRNA, human
• MIRN193 microRNA, human
• MicroRNAs
• RNA, Messenger
• TP73 protein, human
• Tumor Protein p73
• Ubiquitin-Conjugating Enzymes
• ubiquitin-conjugating enzyme UBC9

Topics

• Animals
• Cohort Studies
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Tumor Protein p73 (genetics, metabolism)
• Ubiquitin-Conjugating Enzymes (genetics, metabolism)