Ras mutations in methylclofenapate-induced B6C3F1 and C57BL/10J mouse liver tumours

Area of Science:

• Hepatocarcinogenesis research
• Oncogene activation studies
• Toxicology and carcinogenesis

Background:

• Genotoxic carcinogens frequently activate H-ras oncogenes in mouse liver tumors.
• H-ras mutations are observed in both sensitive and resistant mouse strains.
• The role of H-ras mutations in non-genotoxic carcinogen-induced liver tumors is less understood.

Purpose of the Study:

• To investigate H-ras oncogene mutations in liver tumors induced by the non-genotoxic carcinogen methylclofenapate (MCP).
• To compare the frequency of H-ras mutations in MCP-induced tumors with those induced by genotoxins.
• To assess the involvement of ras oncogenes in hepatocarcinogenesis across different mouse strains.

Main Methods:

• Induction of liver tumors in B6C3F1 and C57BL/10J mice using methylclofenapate (MCP).
• Polymerase chain reaction (PCR) analysis to detect H-ras mutations at codons 61, 12, and 117.
• Nude mouse tumorigenicity (NMT) assay for analyzing tumors lacking codon 61 mutations.

Main Results:

• H-ras codon 61 mutations were found in 11/46 B6C3F1 and 4/31 C57BL/10J MCP-induced liver tumors.
• H-ras codon 117 mutations were identified in two B6C3F1 tumors.
• Ras mutations were detected in some tumors from both sensitive and resistant mouse strains.

Conclusions:

• MCP-induced liver tumors exhibit H-ras codon 61 mutations less frequently than genotoxin-induced tumors.
• H-ras codon 117 mutations, similar to those in spontaneous or other chemically induced tumors, were observed.
• Ras oncogene activation plays a role in methylclofenapate-induced hepatocarcinogenesis, even in resistant mouse strains.