title: Up-regulation of ribosome biogenesis by MIR196A2 genetic variation promotes endometriosis development and progression.
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.
authors.affiliation: Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.|Institute of Environmental Health, China Medical University, Taichung, Taiwan.
authors.forename: Cherry Yin-Yi
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.
authors.forename: Ming-Tsung
authors.initials: MT
authors.lastname: Lai
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.|Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Yang
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chang
authors.affiliation: The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Cheng-Chan
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Mei
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Carmen
authors.initials: C
authors.lastname: Chan
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ching
authors.initials: C
authors.lastname: Chung
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Tseng
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Tritium
authors.initials: T
authors.lastname: Hwang
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.|Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Jim Jinn-Chyuan
authors.initials: JJ
authors.lastname: Sheu
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.|School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D004715:Endometriosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020459:Genes, rRNA; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D017393:RNA Editing; D012318:RNA Polymerase I / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*
chemical_list: C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D012318:RNA Polymerase I
keywords: MIR196A2; endometriosis; ovarian cancer; polymorphism; ribosome biogenesis