Involvement of c-Ski oncoprotein in carcinogenesis of cholangiocacinoma induced by Opisthorchis viverrini and N-nitrosodimethylamine.
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.
Boonmars
Thidarut
T
Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. bthida@kku.ac.th
Wu
Zhiliang
Z
Boonjaruspinyo
Sirintip
S
Puapairoj
Anucha
A
Kaewsamut
Butsara
B
Nagano
Isao
I
Pinlaor
Somchai
S
Yongvanit
Puangrat
P
Wonkchalee
Orasa
O
Juasook
Amornrat
A
Sudsarn
Pakkayanee
P
Srisawangwong
Tuanchai
T
D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008647:Mesocricetus; D009889:Opisthorchiasis / Q000150:complications*; D009891:Opisthorchis / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D002273:Carcinogens; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C060614:SKI protein, human; D004128:Dimethylnitrosamine