title: A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1.
abstract: 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.
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center,  Nanjing Medical University, Nanjing 210029,  China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yu
authors.initials: Y
authors.lastname: Yin
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.forename: Yi
authors.initials: Y
authors.lastname: Jing
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Qi
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Peiper
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C550570:MIRN148 microRNA, human; C550856:MIRN152 microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases