MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma
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AbstractProfiling of microRNA expression in human cancers has highlighted downregulation of miR-145 as a common event in epithelial malignancies. Here, we describe recurrent underexpression of miR-145 in hepatocellular carcinoma (HCC) and the identification of a biological pathway by which miR-145 exerts its functional effects in liver tumorigenesis. In a cohort of 80 HCC patients, quantitative reverse transcription polymerase chain reaction corroborated reduced miR-145 expression in 50% of tumors, which also correlated with a shorter disease-free survival of patients. One HCC tumor analyzed with low endogenous miR-145 was propagated as cell line. This in vitro model HKCI-C2 maintained low miR-145 level and upon restoration of miR-145 expression, a consistent inhibitory effect on cell viability and proliferation was readily found. Flow cytometric analysis indicated that miR-145 re-expression could induce G(2)-M cell cycle arrest and apoptosis. Multiple in silica algorithms predicted that miR-145 could target a number of genes along the insulin-like growth factor (KW) signaling, including insulin receptor substrate (IRS1)-1, IRS2 and insulin-like growth factor 1 receptor. We found protein expression of these putative targets was concordantly downregulated in the presence of miR-145. Luciferase reporter assay further verified direct target association of miR-145 to specific sites of the IRS1 and IRS2 3'-untranslated regions. Subsequent analysis also affirmed miR-145 modulation on the IGF signaling cascade by reducing its downstream mediator, namely the active beta-catenin level. Taken together, our study shows for the first time the pleiotropic effect of miR-145 in targeting multiple components of the oncogenic IGF signaling pathway in HCC.
All Author(s) ListLaw PTY, Ching AKK, Chan AWH, Wong QWL, Wong CK, To KF, Wong N
Journal nameCarcinogenesis
Year2012
Month11
Day1
Volume Number33
Issue Number6
PublisherOXFORD UNIV PRESS
Pages1134 - 1141
ISSN0143-3334
eISSN1460-2180
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesOncology; ONCOLOGY

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