Deleted in Liver Cancer-1 (DLC1): An Emerging Metastasis Suppressor Gene

Abstract

While significant progress continues to be made in the early detection and therapeutic management of primary tumors, the incidence of metastatic disease remains as the major cause of mortality. Accordingly, the development of novel effective therapies that can ameliorate dissemination and secondary tumor growth are a clinical priority. The identification of genetic and functional alterations in cancer cells that affect factors implicated in the metastatic process is critical for designing preventive and therapeutic strategies. Evidence implicating the protein deleted in liver cancer 1 (DLC1), a Rho GTPase activator, in metastasis has accumulated to a point where DLC1 may be considered as a metastasis suppressor gene. This review will present evidence supporting an anti-metastatic role for DLC-1 in several human cancers and discuss the mechanisms contributing to its inhibitory effects. In addition, promising opportunities for therapeutic interventions based on DLC1 function and downstream pathways involved in the metastatic process are considered.

Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers

“…While certain RhoGAPs, most notably DLC1 (14,15), have been characterized and well-validated as tumor suppressors, our findings indicate that this classification is not applicable to all members of the RhoGAP family, as had previously been assumed. Compared to RhoGEFs, RhoGAPs are relatively poorly characterized, particularly with regard to their role in cancer.…”

“…In contrast, RhoGAPs, which stimulate the intrinsic GTPase activity of Rho proteins and return them to an inactive, GDP-bound state (12), are generally presumed to inhibit tumorigenesis (13). For example, the RhoGAP DLC1 is commonly lost in cancer through promoter methylation, genomic deletion, or enhanced protein degradation (14,15). Hence, the prevailing dogma in the field is that Rho GTPases and RhoGEFs are oncogenes in cancer, whereas RhoGAPs are tumor suppressors.…”

Involvement of Rho GAP GRAF1 in maintenance of epithelial phenotype

“…Rho GAP known as DLC1 (“deleted in liver cancer”) is considered as a tumor and metastasis suppressor gene for several human cancers 37 . It is demonstrated that tumor suppressor functions of DLC1 depend on its RhoGAP activity, as well as on some GAP-independent mechanisms 38,39,40 .…”

New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges

“…From that HCC can be divided into the following subgroups: high invasiveness and low invasiveness; high recurrent risk and low current risk; and short-term survival and long-term survival. Many genes or protein biomarkers that have abnormal expression in HCC tissues have been recently reported as shown in Table 1 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”