HRAS , EGFR , MET , and RON Genes Are Recurrently Activated by Provirus Insertion in Liver Tumors Induced by the Retrovirus Myeloblastosis-Associated Virus 2

Abstract

Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci:, ,, and Insertionally mutated genes correlated with tumor type: was hit in HHSs, in ICCs, mostly in ICCs, and mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of and , also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated and closely mimic the structures of oncogenic variants of these genes frequently found in human tumors ( and ). These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.

Identification and Validation of SNP-Containing Genes With Prognostic Value in Gastric Cancer via Integrated Bioinformatics Analysis

“…HRAS functions as an oncogene after activation, and activation commonly occurs through mutations (SNPs, insertions, translocations) and increased expression (23). Diseases related to HRAS include breast cancer, liver cancer, thyroid cancer, and bladder cancer (24)(25)(26)(27). Ectopic expression of HRAS was shown to promote the proliferation, migration, invasion, angiogenesis and clone formation of gastric cancer cells (28).…”

The MSP‐RON pathway regulates liver fibrosis through transforming growth factor beta‐dependent epithelial–mesenchymal transition

“…Accumulating evidence demonstrates that MSP and RON are involved in different kinds of liver disease, such as acute liver injury, nonalcoholic fatty liver and liver cancer 24,29‐31 . Actually, our previous work focused on the expression of MSP in liver cirrhosis, which showed that elevated MSP was an important serological marker for patients with liver cirrhosis.…”