TGF-β in Epithelial to Mesenchymal Transition and Metastasis of Liver Carcinoma.

Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschke-Gasse 8a, 1090 Vienna, Austria. .
Current pharmaceutical design (Impact Factor: 4.41). 05/2012; 18(27):4135-47.
Source: PubMed

ABSTRACT Hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) represent the majority of hepatic malignancies and are among the most frequent causes of cancer deaths worldwide with a rising incidence in western countries. Upon progression of liver cancer, the epithelial to mesenchymal transition (EMT) is considered a key process that drives intrahepatic metastasis. EMT is the transformation of epithelial cells to a mesenchymal phenotype exacerbating motility and invasiveness of various epithelial cell types. In this review we focus on EMT in hepatic fibrosis, HCC and CCC that is governed by the transforming growth factor (TGF)-β signaling. This cytokine has been shown to play diverse and conflicting roles in malignant development, acting as a tumor-suppressor in early cancerogenesis but enhancing tumor dissemination in later stages of tumor progression. Importantly, TGF-β can induce EMT in a variety of cancers including HCC and CCC, even though the complex molecular mechanisms underlying this process are not yet fully understood. We aim at collecting recent findings on the impact of TGF-β-induced EMT in liver carcinoma progression and at discussing new insights on promising drugable targets for future therapeutic approaches against CCC and HCC.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor β (TGF-β) belongs to a class of pleiotropic cytokines that are involved in the processes of embryonic development, wound healing, cell proliferation, and differentiation. Moreover, TGF-β is also regarded as a central regulator in the pathogenesis and development of various liver diseases because it contributes to almost all of the stages of disease progression. A range of liver cells are considered to secrete TGF-β ligands and express related receptors and, consequently, play a crucial role in the progression of liver disease via different signal pathways. In this manuscript, we review the role of the TGF-β signaling pathway in liver disease and the potential of targeting the TGF-β signaling in the pharmacological treatment of liver diseases.
    Pharmacological research : the official journal of the Italian Pharmacological Society. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Liver fibrosis is a progressive condition with serious clinical complications arising from abnormal proliferation and amassing of tough fibrous scar tissue. Macrophages are found in secreting chemokines that recruit fibroblasts and other inflammatory cells, and inflammatory cytokines that activate the hepatic stellate cell (HSC) play an essential event during liver fibrogenesis. The potential of macrophages acts in both pro- and anti-fibrotic capacities followed by related genes of inflammation in coordination with epigenetic modifications in liver fibrogenesis. Areas covered: In this review, we focus on the role of suppressor of cytokine signalling (SOCS) proteins in transcriptional regulation at the level of the chromatin structure and the interaction of SOCS with microRNAs during liver fibrosis. Moreover, we will discuss the different signalling pathways that interact with SOCS-regulated HSC activation. Expert opinion: Although the exact role of SOCS proteins in liver fibrosis has not been fully elucidated, recognition of SOCS proteins and its regulation by these multiple mechanisms may offer new potential targets of liver fibrosis, and provide new understandings of the development of future therapeutic strategies.
    Expert Opinion on Therapeutic Targets 03/2014; · 4.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glioma-associated oncogene homolog-1 (Gli-1) is considered a marker of Hedgehog pathway activation and is associated with the progression of several cancers. We have previously reported that Gli-1 was correlated with invasion and metastasis in hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of Gli-1 in HCC invasion are unclear. In this study, we found that small interfering RNA mediated down-regulation of Gli-1 expression significantly suppressed adhesion, motility, migration, and invasion of both SMMC-7721 and SK-Hep1 cells. Furthermore, down-regulation of Gli-1 significantly reduced expressions and activities of both matrix metalloproteinase (MMP)-2 and MMP-9. In addition, we found that down-regulation of Gli-1 resulted in up-regulation of E-cadherin and concomitant down-regulation of Snail and Vimentin, consistent with inhibition of epithelial-mesenchymal transition (EMT). Taken together, our results suggest that down-regulation of Gli-1 suppresses HCC cell migration and invasion likely through inhibiting expressions and activations of MMP-2, 9 and blocking EMT.
    Molecular and Cellular Biochemistry 05/2014; · 2.33 Impact Factor