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MIR196A2基因变异导致的核糖体生物合成上调促进子宫内膜异位症的发生和发展。

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

作者信息

Chang Cherry Yin-Yi, Lai Ming-Tsung, Chen Yi, Yang Ching-Wen, Chang Hui-Wen, Lu Cheng-Chan, Chen Chih-Mei, Chan Carmen, Chung Ching, Tseng Chun-Cheng, Hwang Tritium, Sheu Jim Jinn-Chyuan, Tsai Fuu-Jen

机构信息

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

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

出版信息

Oncotarget. 2016 Nov 22;7(47):76713-76725. doi: 10.18632/oncotarget.11536.

DOI:10.18632/oncotarget.11536
PMID:27741504
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5363543/
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.

摘要

子宫内膜异位症中已报道有异常的微小RNA（miRNA）表达，且miRNA基因多态性与癌症有关。由于某些卵巢癌起源于子宫内膜异位症，我们对7个与癌症相关的miRNA单核苷酸多态性（MiRSNPs）进行了基因分型，以研究它们在子宫内膜异位症中可能发挥的作用。发现MIR196A2（rs11614913）和MIR100（rs1834306）中的基因变异与子宫内膜异位症的发生发展以及相关临床表型（如不孕和疼痛）有关。对MIR196A2风险等位基因的下游分析显示核糖体RNA编辑和蛋白质合成基因上调，提示核糖体生物合成的过度激活是子宫内膜异位症进展的驱动力。临床研究证实非典型子宫内膜异位症病变中小核仁RNA和核糖体蛋白水平较高，在相关的卵巢透明细胞癌中更为明显。用RNA聚合酶I抑制剂CX5461处理卵巢透明细胞，可抑制细胞生长和迁移，随后使细胞周期停滞在G2/M期并诱导凋亡。因此，我们的研究揭示了在子宫内膜异位症发生发展过程中由癌症相关的MIR196A2风险等位基因触发的一种新的肿瘤发生途径。我们认为抗RNA聚合酶I治疗可能对治疗子宫内膜异位症及相关恶性肿瘤有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/d44551a2bbf3/oncotarget-07-76713-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/6b0de8dd5fad/oncotarget-07-76713-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/1f21119dc9b5/oncotarget-07-76713-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/8f18d5c65725/oncotarget-07-76713-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/19abbf3ac03c/oncotarget-07-76713-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/d44551a2bbf3/oncotarget-07-76713-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/6b0de8dd5fad/oncotarget-07-76713-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/1f21119dc9b5/oncotarget-07-76713-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/8f18d5c65725/oncotarget-07-76713-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/19abbf3ac03c/oncotarget-07-76713-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b8/5363543/d44551a2bbf3/oncotarget-07-76713-g005.jpg

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