The deleted in liver cancer 1 (DLC1) gene has emerged as a novel tumor suppressor downregulated in a variety of tumor types including those of the breast.
The deleted in liver cancer-1 (DLC-1) gene that encodes a Rho GTPase-activating protein with tumor suppressor function is located on chromosome 8p21-22, a region frequently deleted in prostate carcinomas.
That binding, which interferes with the interaction of RhoA-GTP with the RhoGAP domain, reduces the hydrolysis of RhoA-GTP, the binding of other DLC1 ligands, and the colocalization of DLC1 with focal adhesions and attenuates tumor suppressor activity.
Taken together, our results suggest that DLC-1 might be an NPC-related tumor suppressor gene affected by aberrant promoter methylation and gene deletion.
Subsequent studies have demonstrated that DLC-1 is generally expressed in normal human tissues as well as in rats, while it always exists inactivated or even lost in many human cancers, which characterizes DLC-1 as a potential tumor suppressor.
Since DLC‑1 is a candidate tumor suppressor gene, we sought to determine whether DLC‑1 expression is associated with cell proliferation in colon cancer cell lines.
Restoration of DLC1 expression in GBC-SD and NOZ cells significantly reduced cell proliferation, migration in vitro, and the ability of these cells to form tumors in vivo.
Restoration of DLC-1 expression in RCC cells led to Bcl-2 and caspase-3 mediated apoptosis as well as attenuated the ability of the cells to form RCC tumors in athymic nude mice (P<0.05).
Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor cell proliferation and tumorigenesis in both cell lines.
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.
Multivariate analyses indicated that tumor size was the significant independent predictors of OS (p = 0.048); however, only DLC-1 expression was a significant independent predictor of DMFS (p = 0.019).
More than a 10-fold increase in mRNA expression was observed for two previously identified tumor suppressor genes (DLC-1 and DCC) and also for RPIB9 and PCDHGA12.
Lower expression levels of DLC1 indicated a more advanced tumor‑node‑metastasis stage, increased lymph node metastasis, deeper tumor invasion, increased tumor size and a higher rate of distant metastasis.
Loss of the tumour suppressor deleted in liver cancer 1 (DLC1) and the subsequent activation of RhoA were prerequisites for MKL1/2 knockdown-mediated growth arrest.
Increasing evidence has demonstrated that the tumor suppressor gene deleted in liver cancer-1 (DLC1) is tightly implicated in the development and progression of tumors and is verified to be downregulated in a variety of tumors.
In vitro and in vivo analyses indicated that the products of PROSC, SH2D4A, and SORBS3 have tumor-suppressive activities, along with the known tumor suppressor gene DLC1.