Sox9 expression in carcinogenesis and its clinical significance in intrahepatic cholangiocarcinoma.
BACKGROUND
Intrahepatic cholangiocarcinomas develop through a multi-step carcinogenesis. Precancerous lesions are defined as biliary intraepithelial neoplasia. Sex determining region Y-box9 (Sox9) is required for the normal differentiation of the biliary tract.


OBJECTIVE
To evaluate the Sox9 expression in carcinogenesis and its correlation with clinicopathological features in intrahepatic cholangiocarcinoma.


METHODS
Sox9 expression in normal epithelium, biliary intraepithelial neoplasia, and intrahepatic cholangiocarcinoma were investigated immunohistochemically using 43 specimens of intrahepatic cholangiocarcinoma. Sox9 expression in intrahepatic cholangiocarcinoma was compared with the clinicopathological features. The molecular effects of Sox9 were investigated by gene transfection to intrahepatic cholangiocarcinoma cell lines.


RESULTS
Sox9 expression was decreased from the normal epithelium to the biliary intraepithelial neoplasia in a stepwise fashion. In 51.2% (22/43) of the patients with intrahepatic cholangiocarcinoma, Sox9 expression was positive, and Sox9 expression was significantly associated with the biliary infiltration (P=0.034) and poor overall survival (P=0.039). Upregulation of Sox9 promoted the cell migration and invasion, and decreased the E-cadherin expression and increased the vimentin and α-SMA expression in cell lines.


CONCLUSIONS
Decreased Sox9 expression may be related to the early stage of the carcinogenesis of intrahepatic cholangiocarcinoma. Sox9 overexpression in intrahepatic cholangiocarcinoma is related to biliary infiltration and poorer prognosis, and it promotes cell migration and invasion, via the epithelial-to-mesenchymal transition.
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Hajime
H
Matsushima
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Tamotsu
T
Kuroki
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Amane
A
Kitasato
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Tomohiko
T
Adachi
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Takayuki
T
Tanaka
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Masataka
M
Hirabaru
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Takanori
T
Hirayama
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Naoki
N
Kuroshima
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Masaaki
M
Hidaka
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Akihiko
A
Soyama
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Mitsuhisa
M
Takatsuki
Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan.
Naoe
N
Kinoshita
Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Kazunori
K
Sano
Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Noriyuki
N
Nishida
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: sueguchi@nagasaki-u.ac.jp.
Susumu
S
Eguchi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human
Biliary intraepithelial neoplasia; Intrahepatic cholangiocarcinoma; Sox9