期刊
GENES & DEVELOPMENT
卷 22, 期 11, 页码 1439-1444出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1672608
关键词
DLC1; HCC; RNAi; RhoA; mouse model
资金
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [P30 CA008748, P01 CA013106, CA13106] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA008748, P01CA013106] Funding Source: NIH RePORTER
Deletions on chromosome 8p are common in human tumors, suggesting that one or more tumor suppressor genes reside in this region. Deleted in Liver Cancer 1 (DLC1) encodes a Rho-GTPase activating protein and is a candidate 8p tumor suppressor. We show that DLC1 knockdown cooperates with Myc to promote hepatocellular carcinoma in mice, and that reintroduction of wildtype DLC1 into hepatoma cells with low DLC1 levels suppresses tumor growth in situ. Cells with reduced DLC1 protein contain increased GTP-bound RhoA, and enforced expression a constitutively activated RhoA allele mimics DLC1 loss in promoting hepatocellular carcinogenesis. Conversely, down-regulation of RhoA selectively inhibits tumor growth of hepatoma cells with disabled DLC1. Our data validate DLC1 as a potent tumor suppressor gene and suggest that its loss creates a dependence on the RhoA pathway that may be targeted therapeutically.
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