Up-regulation of ribosome biogenesis by MIR196A2 genetic variation promotes endometriosis development and progression

Cherry Yin-Yi Chang, Ming-Tsung Lai, Yi Chen, Ching-Wen Yang, Hui-Wen Chang, Cheng‐Chan Lu, Cheng-Chan Lu, Chih-Mei Chen, Carmen Chan, Ching Chung, Chun-Cheng Tseng, Tritium Hwang, Jim Jinn‐Chyuan Sheu, Jim Jinn-Chyuan Sheu, Fuu‐Jen Tsai, Fuu-Jen Tsai
Oncotarget · 2016 · vol. 7(47) , pp. 76713–76725 · doi:10.18632/oncotarget.11536 · PMID:27741504 · PMC5363543 · W2515148935
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Abstract

// Cherry Yin-Yi Chang 1, 2, * , Ming-Tsung Lai 3, * , Yi Chen 4, * , Ching-Wen Yang 5, 6 , Hui-Wen Chang 7 , Cheng-Chan Lu 5 , Chih-Mei Chen 4 , Carmen Chan 4 , Ching Chung 4 , Chun-Cheng Tseng 6 , Tritium Hwang 6 , Jim Jinn-Chyuan Sheu 4, 6, 8, 9 , Fuu-Jen Tsai 4, 10 1 Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan 2 Institute of Environmental Health, China Medical University, Taichung, Taiwan 3 Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan 4 Human Genetic Center, China Medical University Hospital, Taichung, Taiwan 5 The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan 6 Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan 7 School of Medicine, China Medical University, Taichung, Taiwan 8 School of Chinese Medicine, China Medical University, Taichung, Taiwan 9 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan 10 School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Jim Jinn-Chyuan Sheu, email: [email protected] Fuu-Jen Tsai, email: [email protected] Keywords: ribosome biogenesis, MIR196A2, polymorphism, endometriosis, ovarian cancer Received: February 06, 2016      Accepted: August 09, 2016      Published: September 15, 2016 ABSTRACT Aberrant miRNA expression has been reported in endometriosis and miRNA gene polymorphisms have been linked to cancer. Because certain ovarian cancers arise from endometriosis, we genotyped seven cancer-related miRNA single nucleotide polymorphisms (MiRSNPs) to investigate their possible roles in endometriosis. Genetic variants in MIR196A2 (rs11614913) and MIR100 (rs1834306) were found to be associated with endometriosis development and related clinical phenotypes, such as infertility and pain. Downstream analysis of the MIR196A2 risk allele revealed upregulation of rRNA editing and protein synthesis genes, suggesting hyper-activation of ribosome biogenesis as a driving force for endometriosis progression. Clinical studies confirmed higher levels of small nucleolar RNAs and ribosomal proteins in atypical endometriosis lesions, and this was more pronounced in the associated ovarian clear cell carcinomas. Treating ovarian clear cells with CX5461, an RNA polymerase I inhibitor, suppressed cell growth and mobility followed by cell cycle arrest at G2/M stage and apoptosis. Our study thus uncovered a novel tumorigenesis pathway triggered by the cancer-related MIR196A2 risk allele during endometriosis development and progression. We suggest that anti-RNA polymerase I therapy may be efficacious for treating endometriosis and associated malignancies.

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endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Genetic Predisposition to Disease Genetic Variation MicroRNAs Ribosomes Alleles Case-Control Studies Cell Movement Cell Movement Cell Proliferation Disease Progression Endometrial Neoplasms Endometrial Neoplasms Endometrial Neoplasms Endometrial Neoplasms Endometriosis Endometriosis Female Gene Expression Profiling

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