Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: Potential prospects for combined targeted therapeutics

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is increasing worldwide in an alarming manner. The development of curative therapy for advanced and metastatic HCC is a high clinical priority. The HCC genome is complex and heterogeneous; therefore, the identification of recurrent genomic and related gene alterations is critical for developing clinical applications for diagnosis, prognosis and targeted therapy of the disease. This article focuses on recent research progress and our contribution in identifying and deciphering the role of defined genetic alterations in the pathogenesis of HCC. A significant number of genes that promote or suppress HCC cell growth have been identified at the sites of genomic reorganization. Notwithstanding the accumulation of multiple genetic alterations, highly recurrent changes on a single chromosome can alter the expression of oncogenes and tumor suppressor genes (TSGs) whose deregulation may be sufficient to drive the progression of normal hepatocytes to malignancy. A distinct and highly recurrent pattern of genomic imbalances in HCC includes the loss of DNA copy number (associated with loss of heterozygosity) of TSG-containing chromosome 8p and gain of DNA copy number or regional amplification of protooncogenes on chromosome 8q. Even though 8p is relatively small, it carries an unusually large number of TSGs, while, on the other side, several oncogenes are dispersed along 8q. Compelling evidence demonstrates that DLC1, a potent TSG on 8p, and MYC oncogene on 8q play a critical role in the pathogenesis of human HCC. Direct evidence for their role in the genesis of HCC has been obtained in a mosaic mouse model. Knockdown of DLC1 helps MYC in the induction of hepatoblast transformation in vitro, and in the development of HCC in vivo. Therapeutic interventions, which would simultaneously target signaling pathways governing both DLC1 and MYC functions in hepatocarcinogenesis, could result in progress in the treatment of liver cancer.

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

“…Accumulating evidence also indicates an important role for Myc activation in the progression of hepatomas (22,38,39). We showed here that endogenous Myc activity is regulated by Skp2 in a hepatoma cell line.…”

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

“…This gene is located on chromosome 8p22 and plays a critical role in multiple liver functions. It has been shown that DLC1 is deleted in 40% human HCC 31,32 and that restoration of its expression resulted in inhibition of liver proliferation and reduction of the development of tumors after xenografting HCC cells into nude mice. 33 Exomic sequencing of hepatitis C virus (HCV)-associated HCCs has identified novel mutations in AT-Rich Interactive Domain 2 (ARID2) protein which has been further shown to be a liver tumor suppressor protein.…”

FOXO6 promotes gastric cancer cell tumorigenicity via upregulation of C‐myc

“…Situated upstream of signalling pathways regulating cellular replication/growth as well as apoptosis/growth arrest, C-myc may help integrate processes determining cell numbers and tissue size in physiology and disease [21]. In cancer, c-myc acts as oncogenic roles to promoter tumor formation in vivo and in vitro [21,22].…”

“…The c-myc oncoprotein, as a transcription factor, is a master regulator of genes involved in diverse cellular processes [21]. Situated upstream of signalling pathways regulating cellular replication/growth as well as apoptosis/growth arrest, C-myc may help integrate processes determining cell numbers and tissue size in physiology and disease [21].…”