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A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1.

Authors: Xu, Qing  Jiang, Yue  Yin, Yu  Li, Qi  He, Jun  Jing, Yi  Qi, Yan-Ting  Xu, Qian  Li, Wei  Lu, Bo  Peiper, Stephen S  Jiang, Bing-Hua  Liu, Ling-Zhi 
Citation: Xu Q, etal., J Mol Cell Biol. 2013 Feb;5(1):3-13. doi: 10.1093/jmcb/mjs049. Epub 2012 Aug 29.
Pubmed: (View Article at PubMed) PMID:22935141
DOI: Full-text: DOI:10.1093/jmcb/mjs049

Dysregulation of microRNAs is a common feature in human cancers, including breast cancer (BC). Here we describe the epigenetic regulation of miR-148a and miR-152 and their impact on BC cells. Due to the hypermethylation of CpG island, the expression levels of both miR-148a and miR-152 (miR-148a/152) are decreased in BC tissues and cells. DNMT1, the DNA methyltransferase 1 for the maintenance methylation, is aberrantly up-regulated in BC and its overexpression is responsible for hypermethylation of miR-148a and miR-152 promoters. Intriguingly, we found that DNMT1 expression, which is one of the targets of miR-148a/152, is inversely correlated with the expression levels of miR-148a/152 in BC tissues. Those results lead us to propose a negative feedback regulatory loop between miR-148a/152 and DNMT1 in BC. More importantly, we demonstrate that IGF-IR and IRS1, often overexpressed in BC, are two novel targets of miR-148a/152. Overexpression of miR-148a or miR-152 significantly inhibits BC cell proliferation, colony formation, and tumor angiogenesis via targeting IGF-IR and IRS1 and suppressing their downstream AKT and MAPK/ERK signaling pathways. Our results suggest a novel miR-148a/152-DNMT1 regulatory circuit and reveal that miR-148a and miR-152 act as tumor suppressors by targeting IGF-IR and IRS1, and that restoration of miR-148a/152 expression may provide a strategy for therapeutic application to treat BC patients.

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RGD Object Information
RGD ID: 19165152
Created: 2020-02-04
Species: All species
Last Modified: 2020-02-04
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.