Involvement of c-Ski Oncoprotein in Carcinogenesis of Cholangiocacinoma Induced by Opisthorchis viverrini and N-nitrosodimethylamine

Abstract

Opisthorchiasis is the major public health problem in the endemic areas of Thailand and Laos because Opisthorchis viverrini infection causes serious hepatobiliary diseases including CCA. The molecular mechanism of the CCA carcinogenesis induced by the infection remains obscure. To reveal the potential genes and signaling pathways to involve in the carcinogenesis, the present study investigated the expression of c-Ski, an oncogene, and two TGF-β signaling pathway relative genes, TGF-β and Smad4, during the development of CCA induced by O. viverrini infection in hamster model, and in human opisthorchiasis associated CCA. The results showed that the expression of c-Ski gene was greatly up-regulated during the carcinogenesis of CCA in hamster model. The overexpression of c-Ski was confirmed by immunohistological staining result which showed the increased expression of c-Ski protein in cytoplasm of the epithelial lining of hepatic bile ducts. Moreover, the immunohistological staining of the specimens of human opisthorchiasis associated CCA revealed the up-regulated expression of c-Ski and Smad4 proteins in the cytoplasm of the epithelial lining of hepatic bile ducts and stomal fibrosis respectively. The expression of TGF-β and Smad4 were up-regulated, which expression kinetics was time-dependent of CCA development. These results suggest that c-Ski is likely involved in the carcinogenesis of CCA induced by O. viverrini infection through regulating TGF-β signaling pathway.

Anti-inflammatory effect of prednisolone on the growth of human liver fluke in experimental opisthorchiasis

“…In accordance with our previous reports (Boonmars et al 2010;Boonjaraspinyo et al 2011), pathological changes in the livers Table 1 The effect of prednisolone on histopathological changes, aggregation of inflammatory cells surrounding intrahepatic bile ducts and in liver tissue (Fig. 1a, b, g, h, m, n, s, t) and the infected group (Fig.…”

“…Finally, the metacercariae were isolated and identified under a stereomicroscope. A group of 50 O. viverrini metacercariae was used for each Syrian hamster infection by intragastric intubation (Boonmars et al 2007(Boonmars et al , 2008(Boonmars et al , 2009(Boonmars et al , 2010.…”

MRI and 1H MRS findings of hepatobilary changes and cholangiocarcinoma development in hamsters infected with Opisthorchis viverrini and treated with N-nitrosodimethylamine

“…CCA development has been extensively studied in O. viverriniinfected and NDMA-treated hamsters [35,36]. In O. viverrini infection alone [29], intra-and extra-hepatic bile duct fibrosis and dilatation increased over time but there was no detectable CCA.…”

Overview of biological mechanisms of human carcinogens

“…Expression of c-Ski, TGF-β and Smad4, was significantly up-regulated (Boonmars et al 2011) by Opisthorchis viverrini in a hamster model and humans. There was increased expression of proteins related to stress response, DNA replication and repair, and cell structure (Khoontawad et al 2010).…”