L1 cell adhesion molecule is a novel therapeutic target in intrahepatic cholangiocarcinoma.
OBJECTIVE
Intrahepatic cholangiocarcinoma (ICC), a highly malignant hepatobiliary cancer, has a poor prognosis and is refractory to conventional therapies. The aim of this study is to discover a novel molecular target for the treatment of ICC.


METHODS
To discover novel cancer-associated membrane antigens expressed in ICC cells, we generated monoclonal antibodies (mAb) by immunizing mice with intact ICC cell lines and screened for those that bind to the plasma membrane of ICC cells but not to normal cells. The mAb A10-A3 was selected and its target antigen was identified as the L1 cell adhesion molecule. Expression of L1 in ICC was evaluated by immunohistochemical analysis of tumor samples from 42 ICC patients. The functional significance of L1 expression in the tumor progression of ICC was investigated by L1 suppression, L1 overexpression, and antibody treatment.


RESULTS
L1 was not expressed in normal hepatocytes and intrahepatic bile duct epithelium but highly expressed in 40.5% of ICC patients, remarkably at the invasive front of the tumors. Suppression of L1 with short hairpin RNA significantly decreased proliferation, migration, and invasion of ICC cells in vitro. Consistently, L1 overexpression in ICC cells enhanced proliferation, migration, invasion, and apoptosis resistance. In addition, L1 short hairpin RNA or anti-L1 mAb significantly reduced the tumor growth in nude mice bearing ICC xenograft.


CONCLUSIONS
We identified that L1 is expressed in ICC. L1 plays an important role in the tumor progression of ICC by enhancing cell proliferation, migration, invasion, and survival. L1 may represent a novel therapeutic target for ICC.
Min
Jeong-Ki
JK
Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungnam National University School of Medicine, Daejon, Korea.
Kim
Jin-Man
JM
Li
Shengjin
S
Lee
Jung Whoi
JW
Yoon
Hyunho
H
Ryu
Chun Jeih
CJ
Jeon
Soung Hoo
SH
Lee
Jae-Hyek
JH
Kim
Jin Young
JY
Yoon
Hee Kwan
HK
Lee
Young Kwan
YK
Kim
Bong-Hui
BH
Son
Yeon Sung
YS
Choi
Hong Seo
HS
Lim
Nam-Kyu
NK
Kim
Dae-Ghon
DG
Hong
Hyo Jeong
HJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology; D000937:Antigen-Antibody Reactions; D017209:Apoptosis / Q000276:immunology; D001650:Bile Duct Neoplasms / Q000276:immunology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D039842:Neural Cell Adhesion Molecule L1