The sustained overexpression of c-myc enhances ablation of c-Met/EGFR signaling and progression of liver carcinogenesis in the c-Myc mouse model of liver cancer and in HepG2 cells

Title : The sustained overexpression of c-myc enhances ablation of c-Met/EGFR signaling and progression of liver carcinogenesis in the c-Myc mouse model of liver cancer and in HepG2 cells

Abstract:

The expression of c-Myc, at both gene and protein levels, has been reported in hepatocellular carcinoma (HCC) and different tissue tumors. This protein functions in the control of cellular mass, differentiation, and apoptosis. To better understand the relationship between mitogenic stimulation of hepatocytes and c-Myc activity, a transgenic mouse model of HCC was investigated. Notably, the c-Myc transgene and protein were increased by up to 35-fold in HCC. A time-dependent degradation of the epidermal growth factor receptor (EGFR) was noted with nearly complete loss of this receptor in HCC, despite that the EGF itself was increased. The expression of associated mitogen-activated protein kinases remained unchanged, apart from p-Erk signaling, which was strongly induced. Moreover, dual specific phosphatase 6 (DUSP6) and Ppar?, which inhibit pErk activity, remained at their basal levels. The expression of c- Met receptor and hepatic growth factor was reduced as was that of cyclin D1 and members of TGFß signaling, i.e. Smad 2/3 and Smad 6/7. However, Pcna and transforming growth factors beta were increased suggesting that c-Myc promotes cell cycle progression. This agrees with reduced pro-apoptotic Fas and p53 activity. To investigate the causes of EGFR degradation, the ubiquitin-ligase Nedd4-1 was studied. This protein ubiquinates activated Cdc-42-associated tyrosine kinase (ACK), and when bound to the EGFR, it facilitates its degradation in the presence of EGF. Notably, in HCC, Nedd4-1 and EGF were induced, while ACK and the mutant variant of ACK were reduced. This suggests successful degradation of ACK to provide a molecular rationale for EGFR degradation, and, consequently, maintain a highly differentiated HCC. Taken collectively, these results revealed that using anti-c-myc drugs in HCC may be a promising as anti-cancer strategy and need further research.

Biography:

Mahmoud Mohamed Elalfy Elhefnawy graduated from Ali mobark High School in Dikerness Dakahlia, Egypt. I graduated in veterinary medical Sciences and had master work at Mansoura university in forensic medicine and toxicology. Mahmoud Elhefnawy received a scholarship for PhD in Fraunhofer institute for toxicology and experimental medicine (2008-2011). This PhD degree emphasized Molecular Biology, Genetics and imaging modalities in liver cancer with cooperation with excellent cluster research of pharmaco-toxicogenomics institute, pathology and radiology institutes of medical school of Hannover Germany. I later complete my research in University of Mansoura University, Egypt and still share in education, research and reviewing of forensic medicine and toxicology specialist on Mansoura University till now I have cooperation research with Zigzag university, Alexandria university and also in KSA as Abha University. I share in reviewing and also as editorial board of many journals.