REV1 is implicated in the development of carcinogen-induced lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The somatic mutation hypothesis posits that decreasing carcinogen-induced mutations reduces cancer incidence.
• DNA damage tolerance pathways, like translesion synthesis (TLS), are crucial for cell survival but can promote mutagenesis.
• REV1 is a key protein in the TLS pathway, involved in bypassing DNA damage induced by carcinogens such as benzo[a]pyrene.

Purpose of the Study:

• To investigate the role of REV1 in benzo[a]pyrene-induced mutagenesis and lung tumorigenesis.
• To develop and test an antimutator strategy by reducing REV1 expression.
• To evaluate the potential of targeting REV1 as a cancer prevention strategy.

Main Methods:

• Mouse cells were engineered to reduce REV1 expression using a gene-specific targeting ribozyme.
• Mutagenesis assays were performed using the activated form of benzo[a]pyrene.
• In vivo studies involved aerosol delivery of a REV1-targeting plasmid complexed with polyethyleneimine to mouse lungs.
• REV1 transcript levels were quantified in bronchial epithelium using quantitative real-time PCR.
• Carcinogen-induced lung tumor multiplicity was assessed in treated and control mice.

Main Results:

• REV1 reduction in mouse cells decreased benzo[a]pyrene-induced mutagenesis by over 90%.
• In vivo, REV1 transcript levels in the bronchial epithelium were reduced by 60% following aerosol delivery.
• A significant decrease in the average number of lung tumors per mouse was observed (from 6.4 to 3.7).
• REV1 inhibition led to complete abolition of tumor formation in 27% of exposed mice.

Conclusions:

• REV1 plays a critical role in the development of lung cancer initiated by carcinogens.
• Targeting the translesion synthesis pathway, specifically REV1, is a viable strategy for cancer prevention.
• Modulating TLS pathway components offers novel therapeutic targets for reducing cancer incidence.