Z Gastroenterol 2014; 52 - P_4_04
DOI: 10.1055/s-0033-1360957

Decreased phosphorylated Smad3 at linker site predicts poor prognosis of patients with cholangiocarcinoma

HL Weng 1, S Munker 1, I Koenigsrainer 2, B Sipos 3, A Koenigsrainer 2, S Nadalin 2, S Dooley 1, J Li 4
  • 1Heidelberg University, Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Mannheim, Germany
  • 2Tübingen University, Department of General Surgery and Transplantation, University Hospital Tübingen, Tübingen, Germany
  • 3Tübingen University, Department of Pathology, University Hospital Tübingen, Tübingen, Germany
  • 4University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary Surgery and Visceral Transplantation, Hamburg, Gemrany

Background & Aims: Phosphorylation at C-terminal and linker sites of Smad3 by TGF-β or other factors plays different roles in carcinogenesis. The present study investigated the potential association between phosphorylation at C-terminal/linker sites of Smad3 and clinical characteristics of intrahepatic cholangiocarcinoma (ICC).

Methods: Immunohistochemistry (IHC) staining was performed to detect the levels of TGF-β, p-Smad3C, p-Smad3L(ser204, ser208 and ser213) and cytokeratin19 (CK19) in 40 resected specimens (25 ICC, 10 cirrhosis and 5 hemangioma). The correlation between TGF-β/Smad3C IHC score and clinicopathological characteristics of ICC was evaluated.

Results: In control and cirrhotic tissues, only p-Smad3L(ser213) was specifically present in normal bile duct epithelial cells, hepatic progenitor cells and reactive ducts, whereas the cells were negative for p-Smad3C?. The staining pattern of p-Smad3L(ser213) was highly consistent with CK19 expression. In 25 patients with ICC, levels of p-Smad3L(ser213) were significantly reduced in ICC cancer cells as compared to surrounding non-tumor tissues. Cancer cells of well differentiated ICC keep strong p-Smad3L(ser213) positive staining, as they do for CK19 expression, whereas p-Smad3L(ser213) was significantly reduced in cancer cells of patients with moderate or poor differentiated ICC. ICC patients with high levels of p-Smad3L(ser213) had higher survival times than those with low (p = 0.03). Although statistical significance was not reached, p-Smad3L(ser213) demonstrated a negative correlation with the occurrence of metastasis at admission (p = 0.09) and the development of metastasis during the course of disease (p = 0.07). In contrast to p-Smad3L(ser213), elevated immune positivity of p-Smad3C and TGF-β exhibited in ICC cancer cells compared to surrounding non-tumor tissue. No association was found between p-Smad3C and clinical characteristics.

Conclusions: Cholangiocytes physiologically express p-Smad3L(ser213). Loss or reduction of p-Smad3L(ser213) positive staining predicts poor prognosis for patients with ICC.