Feng, Teng and Dzieran, Johanna and Gu, Xing and Marhenke, Silke and Vogel, Arndt and Machida, Keigo and Weiss, Thomas S. and Ruemmele, Petra and Kollmar, Otto and Hoffmann, Patrick and Graesser, Friedrich and Allgayer, Heike and Fabian, Jasmin and Weng, Hong Lei and Teufel, Andreas and Maass, Thorsten and Meyer, Christoph and Lehmann, Ulrich and Zhu, Cheng and Mertens, Peter R. and Gao, Chun Fang and Dooley, Steven and Meindl-Beinker, Nadja M. (2015) Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma. CLINICAL SCIENCE, 128 (11). pp. 761-774. ISSN 0143-5221, 1470-8736
Full text not available from this repository. (Request a copy)Abstract
Transforming growth factor beta (TGF-beta) is cytostatic towards damage-induced compensatory hepatocyte proliferation. This function is frequently lost during hepatocarcinogenesis, thereby switching the TGF-beta role from tumour suppressor to tumour promoter. In the present study, we investigate Smad7 overexpression as a pathophysiological mechanism for cytostatic TGF-beta 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-beta 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) and disease-free survival (P = 0.0123). Delineating a mechanism for Smad7 transcriptional regulation in HCC, we identified cold-shock Y-box protein-1 (YB-1), a multifunctional transcription factor. YB-1 RNAi reduced TGF-beta-induced and endogenous Smad7 expression in Huh7 and FLC-4 cells respectively. YB-1 and Smad7 mRNA expression levels correlated positively (P < 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-beta actions in a subgroup of HCC cells that may facilitate aspects of tumour progression.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR-BETA; COLLAGEN GENE-EXPRESSION; TGF-BETA; INTERFERON-GAMMA; MICE; HEPATOCARCINOGENESIS; REGENERATION; PROTEIN-1; APOPTOSIS; FIBROSIS; hepatocellular carcinoma (HCC); human tissue; liver cancer; transforming growth factor beta (TGF-beta); Y-box protein-1 (YB-1) |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I Medicine > Lehrstuhl für Kinder- und Jugendmedizin Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Jul 2019 07:19 |
| Last Modified: | 18 Jul 2019 07:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5476 |
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