DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma

Kim, Tai Young; Lee, Sang Eun; Kim, Hwang Phill; Jong, Hyun Soon; Kim, Taeyou; Jung, Mira; Bang, Yung Jue

doi:10.1016/j.bbrc.2007.01.121

Cited by 73 publications

(75 citation statements)

References 28 publications

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“…The Rho-GAP domain of DLC1 is thought to be essential for its growth-inhibitory effect on tumor cells. 22,23 Recently, in lung cancer cells, DLC1 inhibits prostate cancer cell proliferation M Guan et al the Rho-GAP domain of DLC1 was shown to stimulate the GTPase activity of RhoA as well as that of RhoB, RhoC and Cdc42 and inhibit cell proliferation by both Rho-GAP domain-dependent and -independent mechanisms. 31 DLC1 was also recently shown to interact with members of the tensin family of focal adhesion proteins [32][33][34] and demonstrated that suppression of the migration of human lung cancer cells by DLC1 requires cooperation between the Rho-GAP and tensin-binding domains.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 We, therefore, examined whether restoration of DLC1 expression affected the activation status of RhoA in PCA cells. PC-3 and C4-2-B2 cells were deprived of serum and then stimulated with LPA for 20 min, after which the amount of the GTPbound (activated) form of RhoA coupled with a Rhotekin-binding domain peptide was determined.…”

Section: Oncosuppressive Effect Of Dlc1 In Pca Cellsmentioning

confidence: 99%

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Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

et al. 2008

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Our recent study showing highly recurrent loss of function of DLC1 (deleted in liver cancer 1), a tumor suppressor gene in primary prostate carcinoma (PCA), implicates this gene in the pathogenesis of this disease. To evaluate the response of PCA to oncosuppressive activity of DLC1, we examined now the effects of adenoviral vector for human DLC1 transduction into the DLC1-deficient, androgen-independent (AI) and aggressive human PCA cell lines PC-3 and C4-2-B2. Adenovirus-mediated restoration of DLC1 expression inhibited the proliferation, invasiveness and anchorage-independent growth of PC-3 and C4-2-B2 cells in vitro as well as the tumorigenicity of PC-3 cells in nude mice. It also induced cell-cycle arrest, inhibited the activation of RhoA and the formation of actin stress fibers. DLC1 induced apoptosis in C4-2-B2 cells, whereas it did not elicit such an effect in PC-3 cells. The abundance of the antiapoptotic protein Bcl-2 was greater in PC-3 cells than in C4-2-B2 cells, and PC-3 cells were rendered sensitive to DLC1-induced apoptosis by treatment with the Bcl-2 inhibitor HA14-1. These results suggest that adenovirus-mediated DLC1 transfer, alone or together with other agents, such as inhibitors of Bcl-2 or histone deacetylase, might prove effective in the treatment of aggressive, AI-PCA.

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Section: Discussionmentioning

confidence: 99%

Section: Oncosuppressive Effect Of Dlc1 In Pca Cellsmentioning

confidence: 99%

Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

et al. 2008

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“…The RhoGAP domain has been shown to be functionally important to the biological activities of DLC1 tumor suppressor. Loss of Rho-GAP activity via mutation in RhoGAP domain 25,31 or by binding to 14-3-3 proteins has shown to regulate the tumor suppressor activity of DLC1 and facilitates signaling by active Rho. 59 Phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431.…”

Section: Dlc1 Loss Correlates With Poor Prognosismentioning

confidence: 99%

“…11,12,14,[16][17][18][19][20][21][22] Transcriptional reactivation of silenced DLC1 gene in tumor cells suppresses their proliferation and migration, induces apoptosis in vitro, and inhibits tumorigenicity and metastasis in vivo. 16,21,[23][24][25][26][27][28] Initially, the effects of DLC1 as a tumor suppressor were attributed to its RhoGAP activity, which has a significant role in cell growth, cytokinesis, morphogenesis, cell motility, trafficking, organization of cell cytoskeleton, transformation, and metastasis. 21,29 Subsequently, RhoGAPindependent tumor-suppressive mechanisms have also been identified.…”

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confidence: 99%

Loss of DLC1 is an independent prognostic factor in patients with oral squamous cell carcinoma

et al. 2012

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Deleted in liver cancer (DLC1), a Rho GTPase-activating protein, was observed to be differentially expressed in oral squamous cell carcinoma in comparison with normal tissues using tissue proteomics. In the current study, we investigated the clinical significance of loss of DLC1 expression in different stages of development of oral squamous cell carcinoma to determine its potential as a biomarker for oral dysplasia and prognosis of oral squamous cell carcinoma. Immunohistochemical analysis of DLC1 expression was carried out in oral squamous cell carcinoma patients (n ¼ 214), dysplasia (n ¼ 51), hyperplastic squamous mucosa (n ¼ 45), and histologically normal oral tissues (n ¼ 80), and correlated with clinicopathological parameters and disease prognosis over 91 months for oral squamous cell carcinomas. Loss of DLC1 expression was observed in oral squamous cell carcinoma (64%), oral dysplasia (31%), hyperplastic squamous mucosa (22%), and normal mucosa (16%). Significant loss of DLC1 expression was observed in oral squamous cell carcinomas as compared with dysplasia (Po0.001, odds ratio ¼ 3.8, 95% CI ¼ 2.0-7.3), suggesting it may be an important event involved in cancer progression. Among oral squamous cell carcinomas, the loss of DLC1 expression was significantly associated with poor prognosis (P ¼ 0.021, hazards ratio (HR) ¼ 1.8, 95% CI ¼ 1.1-2.9). Multivariate analysis revealed loss of DLC1 (P ¼ 0.023, HR ¼ 2.1, 95% CI ¼ 1.2-3.9) and histopathological grade (P ¼ 0.015, HR ¼ 1.7, 95% CI ¼ 1.1-2.7) to be independent predictors for disease-free survival in oral squamous cell carcinoma patients in comparison with known prognostic factors, viz. tumor stage, nodal status, and overall stage. Loss of DLC1 expression emerged as an important biomarker for predicting patients diagnosed with oral dysplasia at high risk of transformation upon future validation in longitudinal studies. Loss of DLC1 expression is a poor prognostic marker for oral squamous cell carcinoma patients.

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“…The human DLC-1 (deleted in liver cancer) has been known as tumor suppressor showing that DLC-1 inhibits cell growth, colony formation, and invasion capacity in hepatocellular, breast, and non-small cell lung carcinoma (Ng et al, 2000;Yuan et al, 2003a;Kim et al, 2007;Healy et al, 2008). DLC-1 and its rat homolog p122 RhoGAP contain three functional domains such as an amino terminal SAM (sterile α-motif), a central RhoGAP, and a carboxy terminal START (steroidogenic acute regulatory related lipid transfer) domain (Durkin et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional induction of DLC-1 gene through Sp1 sites by histone deacetylase inhibitors in gastric cancer cells

Kim

Jong

et al. 2008

Exp Mol Med

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We previously reported that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, induced DLC-1 mRNA expression and accumulated acetylated histones H3 and H4 associated with the DLC-1 promoter in DLC-1 non-expressing gastric cancer cells. In this study, we demonstrated the molecular mechanisms by which TSA induced the DLC-1 gene expression. Treatment of the gastric cancer cells with TSA activates the DLC-1 promoter activity through Sp1 sites located at -219 and -174 relative to the transcription start site. Electrophoretic mobility-shift assay (EMSA) revealed that Sp1 and Sp3 specifically interact with these Sp1 sites and showed that TSA did not change their binding activities. The ectopic expression of Sp1, but not Sp3, enhances the DLC-1 promoter responsiveness by TSA. Furthermore, the TSA-induced DLC-1 promoter activity was increased by p300 expression and reduced by knockdown of p300. These results demonstrated the requirement of specific Sp1 sites and dependence of Sp1 and p300 for TSA-mediated activation of DLC-1 promoter.

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DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma

Cited by 73 publications

References 28 publications

Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

Loss of DLC1 is an independent prognostic factor in patients with oral squamous cell carcinoma

Transcriptional induction of DLC-1 gene through Sp1 sites by histone deacetylase inhibitors in gastric cancer cells

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