Z Gastroenterol 2012; 50 - P5_13
DOI: 10.1055/s-0031-1295969

Smad7 expression is upregulated in HCC patients and correlates with Smad2 mediated downstream signaling in HCC cell lines

J Dzieran 1, J Fabian 1, X Gu 2, T Weiß 3, C Gao 2, S Dooley 1, NM Meindl-Beinker 1
  • 1Molecular Hepatology – Alcohol Associated Diseases, II. Medical Clinic, Faculty of Medicine at Mannheim, University of Heidelberg, Mannheim
  • 2Department of Laboratory Medicine, Eastern Hepatobiliary Hospital Second Military Medical University, Shanghai, China
  • 3Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Regensburg, Regensburg

Hepatocellular carcinoma (HCC) is the third most deadliest cancer and very heterogenic. Together with often late diagnosis, this leads to the necessity of new treatment strategies. The TGF-ß family regulates a cohourt of cellular processes. Smad7 is a potent inhibitor of canonical TGF-ß signaling. As TGF-ß may fulfil ambiguous functions, it is important to develop a deep understanding about its tumor suppressive vs. promoting effects during cancer development and progression. Frequently occurring mutations of TGF-ß signaling components that may lead to abrogation of the TGF-ß cytostatic response, as found in other cancer types, are seldom in HCC.

We show that Smad7 is overexpressed in 66% of 146 analyzed patient samples, when comparing “normal liver” vs. HCC tissue. To delineate the mechanism, we analyzed 10 HCC cell lines with different TGF-ß responses. Here, Smad7 mRNA levels are strongly varying, but correlate with TGF-ß expression (real time PCR) and inversely with TGF-ß induced Smad2 activation (Western Blot). This suggests a mechanism to reduce canonical TGF-ß signaling, as proven by reduced CAGA reporter activity and TGF-ß target gene expression (e.g. Smad7), therewith protecting tumor cells against cytostatic TGF-ß and anti-metastatic Smad2 functions. In parallel production and secretion of high TGF-ß levels in this setting may enhance tumorigenic Smad independent signaling. To delineate this in further detail, modulation of Smad7 expression and subsequent migration and invasion as well as cytotoxicity assays are currently undertaken.

In summary, we show Smad7 overexpression in human HCC samples and its varying expression in HCC cell lines. Here, Smad7 levels have impact on TGF-ß induced signaling and outcome, thus participating in the switch from cytostatic to tumor promoting response. Further, the different HCC cell lines seem to be representative for the heterogeneity of HCC in individual patients and/or different stages of hepatocarcinogenesis.