Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma.
Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.
Wong
Chun-Ming
CM
Department of Pathology, S.H. Ho Foundation Research Laboratories and Jockey Club Clinical Research Centre, Pokfulam, Hong Kong.
Yam
Judy Wai-Ping
JW
Ching
Yick-Pang
YP
Yau
Tai-On
TO
Leung
Thomas Ho-Yin
TH
Jin
Dong-Yan
DY
Ng
Irene Oi-Lin
IO
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D020690:GTPase-Activating Proteins; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins