Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma. 1620 57

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 wild-type 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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PMID:DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. 1859 73

Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to inhibit mitogenic signaling and suppressing cell proliferation in colonic tumorigenesis. The transcription of DLC1 (deleted in liver cancer), a tumor suppressor gene, is frequently silenced in various types of human cancer. In this study, we postulated that UDCA may inhibit DLC1 protein degradation in hepatocellular carcinoma (HCC) cells, and increased DLC1 expression may suppress HCC cell growth. Human HCC cell lines were used in this study. The methylation status was measured by methylation-specific PCR following sodium bisulfite treatment. Cell proliferation was assessed using an MTS assay. Kinase signaling cascades were evaluated by immunoblot analysis. For assessing ubiquitination, immunoprecipitation analysis was used. To inhibit cellular protein, specific small interfering RNAs (siRNAs) were transfected into cells. DLC1 protein levels increased over time following UDCA treatment. Specifically, UDCA increased the half-life of the DLC1 protein by inhibiting proteasomal degradation of DLC1 without affecting ubiquitination of the DLC1 protein. In addition, HCC cell growth was suppressed following UDCA treatment and this growth suppression was significantly reversed following transfection with DLC1-siRNA. Inhibition of DLC1 increased cellular proliferation; this was reduced after Rho-inhibitor treatment. Finally, RhoA activity was reduced following UDCA treatment; this result was reversed and thus increased following DLC1-siRNA transfection. In conclusion, these results demonstrate that UDCA induces DLC1 protein expression by inhibiting proteasomal DLC1 degradation in a ubiquitin-independent manner, and that DLC1 induction participates in UDCA-induced suppression of HCC cell growth. These observations implicate UDCA as an anti-proliferative agent in HCC.
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PMID:Ursodeoxycholic acid-induced inhibition of DLC1 protein degradation leads to suppression of hepatocellular carcinoma cell growth. 2145 86