MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma.
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.
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ABSTRACT: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.Infectious Agents and Cancer 01/2014; 9:27. · 2.07 Impact Factor
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ABSTRACT: P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.Zeitschrift für Gastroenterologie 01/2014; 7(9):6125-32. · 1.67 Impact Factor
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ABSTRACT: Age-related hearing loss is a progressive sensorineural hearing loss that occurs during aging. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined miRNA gene expression profiles in the lateral wall of two mouse strains, along with exploration of the potential targets of those miRNAs that showed dynamic expression during aging. We show that 95 and 60 miRNAs exhibited differential expression in C57 and CBA mice during aging, respectively. A majority of downregulated miRNAs are known to regulate pathways of cell proliferation and differentiation, while all upregulated miRNAs are known regulators in the pro-apoptotic pathways. By using apoptosis-related gene array and bioinformatic approaches to predict miRNA targets, we identify candidate miRNA-regulated genes that regulate apoptosis pathways in the lateral wall of C57 and CBA mice during aging.PLoS ONE 11/2014; 9(11):e112857. · 3.53 Impact Factor