Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma.
Family members of the connective tissue growth factor, cysteine-rich 61, nephroblastoma over-expressed gene (CCN) encode cysteine-rich secreted proteins with roles in human fibrotic disorders and tumor progression. In this study, we identified a CCN family member, WISP1v, as over-expressed in human cholangiocarcinomas. Genetic analysis of WISP1v was performed on surgically resected specimens of cholangiocarcinoma. The WISP1v biological effects were analyzed using the HuCCT1 human cholangiocarcinoma cell line. The WISP1v gene was expressed in 19 of 39 cholangiocarcinoma tissues (49%) but not in normal livers. Expression of WISP1v was significantly associated with lymphatic and perineural invasion of tumor cells (P <.05), as well as a poor clinical prognosis (P <.01). In the intraductal papillary cholangiocarcinomas, WISP1v was detected only in the cases with duct wall invasion but not in the cases without duct wall invasion (P <.05). No mutation of WISP1v gene was detected in the examined samples. In vitro analysis revealed that WISP1v stimulated the invasive phenotype of cholangiocarcinoma cells with activation of both p38 and p42/p44 mitogen-activated protein kinases (MAPKs). Furthermore, WISP1v-induced cholangiocarcinoma invasion was significantly suppressed by the p38 MAPK inhibitor SB203580 but not by the p42/p44 MAPK kinase (MEK) inhibitor PD98059. Our findings suggest that WISP1v-mediated signaling is involved in the generation of invasive cellular properties and leads to progression of cholangiocarcinoma.
Tanaka
Shinji
S
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. shinjit@surg2.med.kyushu-u.ac.jp
Sugimachi
Keishi
K
Kameyama
Toshifumi
T
Maehara
Shin-Ichiro
S
Shirabe
Ken
K
Shimada
Mitsuo
M
Wands
Jack R
JR
Maehara
Yoshihiko
Y
D016475:3T3 Cells; D000368:Aged; D000818:Animals; D001650:Bile Duct Neoplasms / Q000473:pathology / Q000503:physiopathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D055511:CCN Intercellular Signaling Proteins; D018281:Cholangiocarcinoma / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D022821:RNA Splice Sites; D048051:p38 Mitogen-Activated Protein Kinases
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492067:CCN4 protein, mouse; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D022821:RNA Splice Sites; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases