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

Tripathi, Satyendra Chandra; Kaur, Jasbir; Matta, Ajay; Gao, Xin; Sun, Bin; Chauhan, Shyam S.; Thakar, Alok; Shukla, Nootan Kumar; Duggal, Ritu; Choudhary, Ajoy Roy; Dattagupta, S; Sharma, Mehar Chand; Ralhan, Ranju; Siu, Kin Wai Michael

doi:10.1038/modpathol.2011.145

Cited by 14 publications

(5 citation statements)

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“…This result is consistent with a previous report in lung cancer that the degree of DLC1 methylation was inversely correlated with the extent of disease (45). A recent report also identified low DLC1 expression as a poor prognostic factor in oral squamous cell cancer (46). The results suggest DLC1 inactivation contributes to cancer progression, probably via the combined effects of its RhoGAP-dependent and RhoGAP-independent activities.…”

Section: Discussionmentioning

confidence: 97%

Functional Interaction of Tumor Suppressor DLC1 and Caveolin-1 in Cancer Cells

Qian

Papageorge

et al. 2012

Cancer Research

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Deleted in liver cancer 1 (DLC1), a tumor suppressor gene frequently inactivated in non-small cell lung cancer (NSCLC) and other malignancies, encodes a multidomain protein with a RhoGTPase-activating (RhoGAP) domain and a StAR-related lipid transfer (START) domain. However, no interacting macromolecule has been mapped to the DLC1 START domain. Caveolin-1 (CAV1) functions as a tumor suppressor in most contexts and forms a complex with DLC1. Here, we have mapped the region of DLC1 required for interaction with CAV1 to the DLC1 START domain. Mutation of the DLC1 START domain disrupted the interaction and co-localization with CAV1. Moreover, DLC1 with a START domain mutation failed to suppress neoplastic growth, although it negatively regulated active Rho. CAV1 and DLC1 expression levels were correlated in two public datasets of NSCLC lines and in two independent publicly available mRNA expression datasets of NSCLC tumors. Clinically, low DLC1 expression predicted a poor clinical outcome in patients with lung cancer. Together, our findings indicate that complex formation between the DLC1 START domain and CAV1 contributes to DLC1 tumor suppression via a RhoGAP-independent mechanism, and suggest that DLC1 inactivation probably contributes to cancer progression.

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Section: Discussionmentioning

confidence: 97%

Functional Interaction of Tumor Suppressor DLC1 and Caveolin-1 in Cancer Cells

Qian

Papageorge

et al. 2012

Cancer Research

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“…To determine a suitable cutoff point for the proportion of tumour cells with recognised staining alteration and dichotomising the level of immunohistochemical staining into either high or low expression groups, we used a receiver operating characteristic (ROC) curve according to the previous report ( Tripathi et al , 2012 ) with modifications. The values of the proportions of tumour cells with recognised staining alteration as a continuous variable and survival (alive or dead at the median follow-up time) as a binary variable were subjected to ROC analysis.…”

Section: Methodsmentioning

confidence: 99%

Prognostic significance of epithelial–mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray

et al. 2014

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Background:Epithelial–mesenchymal transition (EMT) is characterised by the loss of cell-to-cell adhesion and gaining of mesenchymal phenotypes. Epithelial–mesenchymal transition is proposed to occur in various developmental processes and cancer progression. ‘Cadherin switch', a process in which cells shift to express different isoforms of the cadherin transmembrane protein and usually refers to a switch from the expression of E-cadherin to N-cadherin, is one aspect of EMT and can have a profound effect on tumour invasion/metastasis. The aim of this study was to investigate the clinicopathological significance of EMT-related proteins and cadherin switch in extrahepatic cholangiocarcinoma (EHCC).Methods:We investigated the association between altered expression of 12 EMT-related proteins and clinical outcomes in patients with EHCC (n=117) using immunohistochemistry on tissue microarrays.Results:Univariate and multivariate analyses revealed that, in addition to N classification (P=0.0420), the expression of E-cadherin (P=0.0208), N-cadherin (P=0.0038) and S100A4 (P=0.0157) was each an independent and a significant prognostic factor. We also demonstrated that cadherin switch was independently associated with poor prognosis (P=0.0143) in patients with EHCC.Conclusions:These results may provide novel information for selection of patients with EHCC who require adjuvant therapy and strict surveillance.

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“…10 DLC1 was mapped to chromosome 8p21.3-22, a region frequently deleted in many solid tumors, including liver cancer, but has later also been found to be silenced by other, mainly epigenetic, mechanisms. [10][11][12] Since its initial discovery, several studies have reported DLC1 downregulation in a number of malignancies including breast, renal, lung, nasopharyngeal, esophageal, cervical, prostate, colorectal, oral squamous cell, and gastric carcinomas, as well as in multiple myelomas and lymphomas, [13][14][15][16][17][18][19][20][21][22][23] and these studies together with recent in vitro and in vivo studies have confirmed the role of DLC1 as a bona fide tumor suppressor. [24][25][26] In addition to containing a RhoGAP domain, responsible for catalyzing the hydrolysis of GTP bound to RhoA, RhoB, RhoC, and Cdc42, DLC1 also contains a steroidogenic acute regulatoryrelated lipid transfer domain, a sterile alpha motif domain, and a focal adhesion-targeting (FAT) domain.…”

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confidence: 93%

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival

et al. 2014

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Deleted in Liver Cancer-1 (DLC1) is a Rho-GTPase-activating protein known to be downregulated and function as a tumor suppressor in numerous solid and hematological cancers. Its expression status in melanoma is currently unknown however, prompting us to examine this. Using immunohistochemistry and tissue microarrays containing a large set of melanocytic lesions (n ¼ 539), we examined the expression profile of DLC1 in melanoma progression, as well as the association between DLC1 and patient survival. We detected both cytoplasmic and nuclear DLC1 expression, and found that whereas cytoplasmic DLC1 was significantly downregulated in metastatic melanoma compared with nevi and primary melanoma, nuclear DLC1 expression was significantly down in primary melanoma compared with nevi, and then further down in metastatic melanoma. Loss of cytoplasmic DLC1 was significantly associated with poorer overall and disease-specific 5-year survival rates of all melanoma (Po0.001 and P ¼ 0.001, respectively) and metastatic melanoma patients (P ¼ 0.020 and 0.008, respectively), and similar results were seen for nuclear DLC1 (Po0.001 for both overall and disease-specific survival for all melanoma patients, and P ¼ 0.004 for metastatic melanoma patients). Next, we examined the correlation between cytoplasmic and nuclear DLC1 and found that concomitant loss of both forms was associated with the worst outcome for metastatic melanoma patients (P ¼ 0.013 and P ¼ 0.008 for overall and disease-specific 5-year survival, respectively). Finally, multivariate Cox regression analysis determined that strong cytoplasmic and nuclear DLC1 expression was a favorable independent prognostic factor for all melanoma (HR, 0.61; 95% CI, 0.42-0.88; P ¼ 0.008) and metastatic melanoma patients (HR, 0.42; 95% CI, 0.23-0.77; P ¼ 0.005). Although more research still needs to be done on the topic, these preliminary results support the hypothesis that DLC1 is a tumor suppressor in melanoma. Modern Pathology (2014Pathology ( ) 27, 1203Pathology ( -1211 doi:10.1038/modpathol.2013 published online 21 February 2014 Keywords: DLC1; immunohistochemistry; melanoma; metastasis; rhogap; tissue microarray; tumor suppressorThe incidence of cutaneous melanoma has been steadily increasing in the non-Hispanic White population worldwide since the 1950s. 1 In the United States, incidence rates have increased by an average 2.8% per annum since 1992 in nonHispanic Whites, currently making it the fifth and seventh most commonly diagnosed cancer in men and women, respectively. 2 Although melanoma accounts for less than 5% of all skin cancers, it is responsible for over 80% of all skin cancer-related deaths. 2 These numbers are greatly attributable to the high metastatic potential of melanoma, and are reflected by a 5-year survival rate of only 5-16% for patients with distant metastases compared with a rate well above 90% for patients with early-stage, localized melanoma. [2][3][4][5] Rho-GTPases belong to the small GTPase family of proteins, and are commonly implicated in the progr...

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

Cited by 14 publications

References 55 publications

Functional Interaction of Tumor Suppressor DLC1 and Caveolin-1 in Cancer Cells

Functional Interaction of Tumor Suppressor DLC1 and Caveolin-1 in Cancer Cells

Prognostic significance of epithelial–mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival

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