Oncotarget

Research Papers:

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, Chih-Mei Chen, Carmen Chan, Ching Chung, Chun-Cheng Tseng, Tritium Hwang, Jim Jinn-Chyuan Sheu _ and Fuu-Jen Tsai

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Oncotarget. 2016; 7:76713-76725. https://doi.org/10.18632/oncotarget.11536

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Abstract

Cherry Yin-Yi Chang1,2,*, Ming-Tsung Lai3,*, Yi Chen4,*, Ching-Wen Yang5,6, Hui-Wen Chang7, Cheng-Chan Lu5, Chih-Mei Chen4, Carmen Chan4, Ching Chung4, Chun-Cheng Tseng6, Tritium Hwang6, Jim Jinn-Chyuan Sheu4,6,8,9, Fuu-Jen Tsai4,10

1Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan

2Institute of Environmental Health, China Medical University, Taichung, Taiwan

3Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan

4Human Genetic Center, China Medical University Hospital, Taichung, Taiwan

5The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan

6Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan

7School of Medicine, China Medical University, Taichung, Taiwan

8School of Chinese Medicine, China Medical University, Taichung, Taiwan

9Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

10School 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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