Comparative analysis of TGF-beta/Smad signaling dependent cytostasis in human hepatocellular carcinoma cell lines


Hepatocellular carcinoma (HCC) is a major public health problem due to increased incidence, late diagnosis and limited treatment options. TGF-beta is known to provide cytostatic signals during early stages of liver damage and regeneration, but exerts tumor promoting effects in onset and progression of liver cancer. To understand the mechanistic background of such a switch, we systematically correlated loss of cytostatic TGF-beta effects with strength and dynamics of its downstream signaling in 10 HCC cell lines. We demonstrate that TGF-beta inhibits proliferation and induces apoptosis in cell lines with low endogenous levels of TGF-beta and Smad7 and strong transcriptional Smad3 activity (PLC/PRF/5, HepG2, Hep3B, HuH7), previously characterized to express early TGF-beta signatures correlated with better outcome in HCC patients. TGF-beta dependent cytostasis is blunted in another group of cell lines (HLE, HLF, FLC-4) expressing high amounts of TGF-beta and Smad7 and showing significantly reduced Smad3 signaling. Of those, HLE and HLF exhibit late TGF-beta signatures, which is associated with bad prognosis in HCC patients. RNAi with Smad3 blunted cytostatic effects in PLC/PRF/5, Hep3B and HuH7. HCC-M and HCC-T represent a third group of cell lines lacking cytostatic TGF-beta signaling despite strong and prolonged Smad3 phosphorylation and low Smad7 and TGF-beta expression. Inhibitory linker phosphorylation, as in HCC-T, may disrupt C-terminally phosphorylated Smad3 function. In summary, we assort 10 HCC cell lines in at least two clusters with respect to TGF-beta sensitivity. Cell lines responsive to the TGF-beta cytostatic program, which recapitulate early stage of liver carcinogenesis exhibit transcriptional Smad3 activity. Those with disturbed TGF-beta/Smad3 signaling are insensitive to TGF-beta dependent cytostasis and might represent late stage of the disease. Regulation of this switch remains complex and cell line specific. These features may be relevant to discriminate stage dependent TGF-beta functions for the design of efficient TGF-beta directed therapy in liver cancer.


Projects: A3.2: Cross-talk of signaling pathways and endocytic machinery in hepato...

PLoS One
PLoS One. 2013 Aug 22;8(8):e72252. doi: 10.1371/journal.pone.0072252. eCollection 2013.
22nd Aug 2013

J. Dzieran, J. Fabian, T. Feng, C. Coulouarn, I. Ilkavets, A. Kyselova, K. Breuhahn, S. Dooley, N. M. Meindl-Beinker

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  • Created: 27th Jul 2015 at 07:19

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