Deleted in Liver Cancer 2 (DLC2) Was Dispensable for Development and Its Deficiency Did Not Aggravate Hepatocarcinogenesis

Abstract

DLC2 (deleted in liver cancer 2), a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, which is essential for embryonic development, DLC2 was dispensable for embryonic development and DLC2-deficient mice could survive to adulthood. We also did not observe a higher incidence of liver tumor formation or diethylnitrosamine (DEN)-induced hepatocarcinogenesis in DLC2-deficient mice. However, we observed that DLC2-deficient mice were smaller and had less adipose tissue than the wild type mice. These phenotypes were not due to reduction of cell size or defect in adipogenesis, as observed in the 190B RhoGAP-deficient mouse model. Together, these results suggest that deficiency in DLC2 alone does not enhance hepatocarcinogenesis.

DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma

“…On the other hand, a study conducted by Yau et al investigated the role of DLC2 by generating DLC2-deficient mice. The mice that were defective in DLC2 were able to survive to adulthood unlike the knockout of DLC1 which led to embryonic lethality (15).…”

“…GAPs belong to a specific family of GTPases that accelerate the rate of GTP hydrolysis by up to 10 5 times (14). Hence, a tumor suppressor role has been suggested for GAPs counteracting the oncogenic potential of Rho proteins (15). Since the identification of the first RhoGAP (16) more than 50 RhoGAPs in the human genome were character-DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma…”

START-GAP/DLC Family Proteins: Molecular Mechanisms for Anti-Tumor Activities

“…Neither did the authors observe a higher incidence of liver tumor formation in the START-GAP2/DLC2 gene knockout mice. Nevertheless, they reported smaller phenotype with less formation of adipose tissue [59].…”

“…Although the START-GAP1/DLC1 gene deficient mice were embryonic lethal, deletion of the START-GAP2/DLC2 gene from mice resulted in survival to adulthood, indicating that the gene, unlike the START-GAP1/DLC1 gene, was dispensable for embryonic development [59]. Neither did the authors observe a higher incidence of liver tumor formation in the START-GAP2/DLC2 gene knockout mice.…”

The mammalian START domain protein family in lipid transport in health and disease

“…However, STARD13/DLC-2 and STARD8/DLC-3 cannot compensate for loss of STARD12/DLC-1. Recent reports characterizing STARD13/DLC-2 knockout mice show that the mice are healthy and fertile with no overt phenotype (Yau et al 2009, Lin et al 2010. The knockout mice were not more susceptible to spontaneous tumors or induced hepatocarcinogenesis, indicating potential compensatory effects of the other DLCs for tumor suppressor activity or possible requirement for a 'second hit' to promote tumor formation (Yau et al 2009, Lin et al 2010.…”