Z Gastroenterol 2012; 50 - P5_40
DOI: 10.1055/s-0031-1295996

TGF-β1 contributes to intrahepatic cholangiocarcinoma via Smad dependent and independent pathways

S Munker 1, Y Liu 1, C Meyer 1, S Dooley 1, J Li 2, H Weng 1
  • 1II. Medizinische Klinik Universtitätsklinikum Mannheim, Universitäts Heidelberg, Mannheim, Germany
  • 2University Department of General, Visceral and Transplant Surgery, Tübingen

Aims: Incidence of intrahepatic cholangiocarcinoma (ICC) rises in western countries. However, unlike hepatocellular carcinoma, the morbidity and mortality of ICC still remains unchanged. So far, only few studies focus on the biological characteristics ICC. TGF-β1 plays a dual role in the progression of human cancer and has been implied to be a major force in ICC. In the present study, we investigated the role of TGF-β1 canonical and non canonical signaling pathways in ICC.

Methods: Immunohistochemical staining for TGF-β1 and P-Smad2/3 was performed in 25 paraffin-embedded cholangiocarcinoma specimens paired with adjacent non-cancerous tissue. TFK–1, a cholangiocellular cell line was used for assessing the impact of TGF-β1 on proliferation. Knockdown experiments by RNAi and Adenoviral overexpression of Smad2 and Smad3 were used to investigate the importance of the canonical signalling pathway. Specific inhibitors were used for blockage of the non-canonical pathways.

Results: Compared with surrounding non-tumor tissues, cancer cells showed strong positivity for TGF-β1 and P-Smad2/3C staining in all 25 ICC patients investigated. Further, Smad3C activation is stronger in samples with lower grading, whereas Smad2C activation correlates positively to cholangiocarcinoma with higher grading. In vitro, RNAi and Adenoviral experiments revealed that TGF-β1 dependent expression of p21, a marker of cell cycle arrest, is Smad3 dependent. However, TGF-β dependant downregulation of PCNA, a marker for proliferation, was independent of either Smad2 and Smad3. TGF-β1 mediated mitoinhibition is associated with the non-canonical TGF-β pathway.

Conclusions: Smad2 activation appears to be connected to a better prognosis of cholangiocarcinoma, whereas Smad3 activation is connected to poorer grading and prognosis. Mitoinhibitory effects of TGF-β1 in cholangiocarcinoma are mediated via Smad dependent and independent signaling pathways.

Smad - cholangiocarcinoma - tgf-beta