Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors

Abstract

Abstract. Several years after the isolation of deleted in liver cancer 1 (DLC-1), a gene that encodes a Rho GTPase activating protein, the closely related DLC-2 gene was identified. DLC-1 and DLC-2 are ~50% identical and share the same SAM-RhoGAP-START domain organization. Since DLC-1 and -2 are located at chromosome regions that are commonly deleted in cancer cells and have been found to function as tumor suppressor genes, we sought to compare their expression profiles in several common types of cancer and to determine whether dlc1 and dlc2 proteins cooperate in tumor development. Using cancer-profiling arrays, we detected for the first time down-regulation of DLC-1 expression in renal, uterine and rectal cancers and down-regulation of DLC-2 expression in lung, ovarian, renal, breast, uterine, gastric, colon and rectal tumors. Since DLC-1 also functions as a metastasis suppressor gene in breast cancer, DLC-1 and DLC-2 expression were examined in a series of primary ductal carcinomas derived from patients with regional lymph node metastases. Using quantitative RT-PCR we detected a significantly lower expression of DLC-1 and DLC-2 in high percentage of tumors, suggesting that deficiency of either DLC gene facilitates dissemination of breast carcinoma cells to secondary sites. We examined DLC-2 expression in DLC-1-negative cell lines derived from human breast, non-small cell lung, and hepatocellular carcinomas, that could be rendered less or non-tumorigenic by ectopic expression of DLC-1. DLC-2 transcripts were detected in all cell lines, indicating that none of the cells were deficient in both members of the DLC family. This comparative expression analysis of DLC-1 and -2 identifies down-regulation of the two emerging bona fide tumor suppressor genes in additional types of solid tumors. The large spectrum of cancers with dysregulated DLC genes underlines the involvement of this family of genes in cancer development.

Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth

“…Hybridization of the filter to 32 P-labeled probes and analysis of the data were performed as described previously (Ullmannova and Popescu, 2006).…”

“…Human cancer cell lines were obtained and cultured as described previously (Guan et al, 2006;Ullmannova and Popescu, 2006), and total RNA was isolated using the TRIzol reagent (Invitrogen, Carlsbad, CA, USA) or the RNeasy Mini Kit (Qiagen, Valencia, CA, USA). Total RNA from normal human liver, mammary gland and prostate were purchased from Stratagene (La Jolla, CA, USA) or Clontech (Mountain View, CA, USA).…”

Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities

“…Its expression is frequently downregulated or silenced in various solid tumors and hematologic malignancies, predominantly by promoter methylation (6)(7)(8)(9)(10)(11)(12)(13). Ectopic reexpression in DLC1-deficient cancer cell lines can suppress cell proliferation, induce apoptosis, and reduce tumorigenicity.…”

“…They have been less intensively examined, but their expression is also down-regulated in a spectrum of tumors (11,17). All three DLC genes encode proteins that are Ϸ1,100 aa, with three recognized motifs: (i) a sterile ␣ motif (SAM; other SAM motifs are often implicated in protein-protein interactions), (ii) a RhoGAP catalytic domain, and (iii) a START (STAR-related lipid transfer) domain.…”

The regulation of rhoA by stard 13 in focal adhesions is essential for astrocytoma cell motility. (c2013)

“…Beside its tumor suppressor characteristic, it was also found to have Rho-GAP function, where it was demonstrated to inhibit the Rho-mediated assembly of actin stress fibers (Ching et al, 2003). StarD13 shares 64% homology with DLC1, another member of the DLC family (Ullmannova & Popescu, 2006). StarD13 consists of an Nterminal SAM motif and a C-terminal START domain.…”