Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma
Abstract:
Transforming growth factor β (TGF-β) is cytostatic towards damage-induced compensatory hepatocyte proliferation. This function is frequently lost during hepatocarcinogenesis, thereby switching the TGF-β role from tumour suppressor to tumour promoter. In the present study, we investigate Smad7 overexpression as a pathophysiological mechanism for cytostatic TGF-β inhibition in liver damage and hepatocellular carcinoma (HCC). Transgenic hepatocyte-specific Smad7 overexpression in damaged liver of fumarylacetoacetate hydrolase (FAH)-deficient mice increased compensatory proliferation of hepatocytes. Similarly, modulation of Smad7 expression changed the sensitivity of Huh7, FLC-4, HLE and HLF HCC cell lines for cytostatic TGF-β effects. In our cohort of 140 HCC patients, Smad7 transcripts were elevated in 41.4% of HCC samples as compared with adjacent tissue, with significant positive correlation to tumour size, whereas low Smad7 expression levels were significantly associated with worse clinical outcome. Univariate and multivariate analyses indicate Smad7 levels as an independent predictor for overall (P<0.001)><0.0001). Furthermore, nuclear co-localization of Smad7 and YB-1 proteins was present in cancer cells of those patients. In summary, the present study provides a YB-1/Smad7-mediated mechanism that interferes with anti-proliferative/tumour-suppressive TGF-β actions in a subgroup of HCC cells that may facilitate aspects of tumour progression.
Projects: A2.1: Multi-level regulation of signalling pathways important for primin..., B2.3: Effect of hepatic stellate cells on hepatocyte polarity and transd...
Clin. Sci.
Clin. Sci. 128(11): 761-74
21st Jan 2015
Teng Feng, Johanna Dzieran, Xing Gu, Silke Marhenke, Arndt Vogel, Keigo Machida, Thomas S Weiss, Petra Ruemmele, Otto Kollmar, Patrick Hoffmann, Friedrich Grässer, Heike Allgayer, Jasmin Fabian, Hong Lei Weng, Andreas Teufel, Thorsten Maass, Christoph Meyer, Ulrich Lehmann, Cheng Zhu, Peter R Mertens, Chun Fang Gao, Steven Dooley, Nadja M Meindl-Beinker
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