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

• DOI: 10.1093/jmcb/mjs049
• Publication Date: 2012-08-31T00:31:30Z
• Authors: Qing Xu; Yue Jiang; Yu Yin; Qi Li; Jun He; Yi Jing; Yan-Ting Qi; Qian Xu; Wei Li; Bo Lu; Stephen S. Peiper; Bing-Hua Jiang; Ling-Zhi Liu
• Keywords: Adult; DNA (Cytosine-5-)-Methyltransferase 1; 0303 health sciences; Neovascularization, Pathologic; Breast Neoplasms; DNA Methylation; Middle Aged; Hypoxia-Inducible Factor 1, alpha Subunit; Gene Expression Regulation, Neoplastic; MicroRNAs; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Insulin Receptor Substrate Proteins; Humans; Female; DNA (Cytosine-5-)-Methyltransferases; Mitogen-Activated Protein Kinases; Neoplasm Grading; Extracellular Signal-Regulated MAP Kinases; Aged; Cell Proliferation

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.