Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma.
Hepatocellular carcinoma (HCC) is a lethal malignancy for which there are no effective therapies. To develop rational therapeutic approaches for treating this disease, we are performing proof-of-principle studies targeting molecules crucial for the development of HCC. Here, we show that cadherin-17 (CDH17) adhesion molecule is up-regulated in human liver cancers and can transform premalignant liver progenitor cells to produce liver carcinomas in mice. RNA interference-mediated knockdown of CDH17 inhibited proliferation of both primary and highly metastatic HCC cell lines in vitro and in vivo. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt signaling, because growth inhibition and cell death were accompanied by relocalization of beta-catenin to the cytoplasm and a concomitant reduction in cyclin D1 and an increase in retinoblastoma.


CONCLUSIONS
Our results identify CDH17 as a novel oncogene in HCC and suggest that CDH17 is a biomarker and attractive therapeutic target for this aggressive malignancy.
Liu
Ling Xiao
LX
Department of Surgery and Center for Cancer Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Lee
Nikki P
NP
Chan
Vivian W
VW
Xue
Wen
W
Zender
Lars
L
Zhang
Chunsheng
C
Mao
Mao
M
Dai
Hongyue
H
Wang
Xiao Lin
XL
Xu
Michelle Z
MZ
Lee
Terence K
TK
Ng
Irene O
IO
Chen
Yangchao
Y
Kung
Hsiang-fu
HF
Lowe
Scott W
SW
Poon
Ronnie T P
RT
Wang
Jian Hua
JH
Luk
John M
JM
D000328:Adult; D000368:Aged; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
C490584:CDH17 protein, human; D015820:Cadherins; C490585:Cdh17 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin
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