Article

MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma.

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Carcinogenesis (Impact Factor: 5.27). 03/2012; 33(6):1134-41. DOI: 10.1093/carcin/bgs130
Source: PubMed

ABSTRACT Profiling 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 silico algorithms predicted that miR-145 could target a number of genes along the insulin-like growth factor (IGF) 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 β-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.

0 Followers
 · 
150 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Successful implantation requires the synchronization of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk between the embryo and the endometrium remain elusive, however recent studies have revealed alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure; one of the altered miRs is miR-145. We assessed the role of miR-145 and its target, IGF1R, in early implantation. miR-145 overexpression and IGF1R knockdown were achieved in Ishikawa endometrial cells. QPCR, western blotting and 3'UTR luciferase reporter assays confirmed that IGF1R is a direct target of miR-145 in the endometrium. Attachment of mouse embryos or IGF-I-coated beads to endometrial epithelial cells was used to study the effects of altered miR-145 and/or IGF1R expression on early implantation events. miR-145 overexpression or specific reduction of IGF1R impaired attachment in both cases. miR-145/IGF1R target protectors prevented miR-145-mediated reduction in IGF1R and reversed the effect of miR-145 overexpression on attachment. The data demonstrate that miR-145 influences embryo attachment by reducing the level of IGF1R in endometrium.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The insulin-like growth factor 1 (IGF-1) signaling pathway regulates critical biological processes including development, homeostasis, and aging. Dysregulation of this pathway has been implicated in a myriad of diseases such as cancers, neurodegenerative diseases, and metabolic disorders, making the IGF-1 signaling pathway a prime target to develop therapeutic and intervention strategies. Recently, small non-coding RNA molecules in ∼22 nucleotide length, microRNAs (miRNAs), have emerged as a new regulator of biological processes in virtually all organ systems and increasing studies are linking altered miRNA function to disease mechanisms. A miRNA binds to 3'UTRs of multiple target genes and coordinately downregulates their expression, thereby exerting a profound influence on gene regulatory networks. Here we review the components of the IGF-1 signaling pathway that are known targets of miRNA regulation, and highlight recent studies that suggest therapeutic potential of these miRNAs against various diseases.
    Frontiers in Genetics 01/2014; 5:472. DOI:10.3389/fgene.2014.00472
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNA-205 (miRNA-205) was revealed as an attractive prognostic tumour biomarker in recent studies. However, the results of different studies have been inconsistent. We conducted a meta-analysis to elucidate the precise predictive value of miRNA-205 in various human malignant neoplasms. Meta-analysis. Qualified studies were identified up to 5 June 2014 by performing online searches in PubMed, EMBASE and Web of Science, and additional quality evaluations. Seventeen eligible studies with 4827 patients were ultimately enrolled in this meta-analysis. The heterogeneity between studies was assessed using I(2) statistics. Pooled HRs with 95% CIs for patient survival and disease recurrence were calculated to investigate the correlation between miRNA-205 expression and cancer prognosis. Our results indicate that elevated miRNA-205 was significantly associated with enhanced overall survival in the breast cancer subgroup (HR=0.78, 95% CI 0.67 to 0.91) and superior disease-free survival/recurrence-free survival in the adenocarcinoma subgroup (HR=0.68, 95% CI 0.49 to 0.94). miRNA-205 is a promising biomarker for predicting the recurrence and progression of patients with adenocarcinomas or breast cancer. Owing to its complex roles, further relevant studies are warranted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    BMJ Open 01/2015; 5(1):e006244. DOI:10.1136/bmjopen-2014-006244 · 2.06 Impact Factor