TOP2 and NOS2 Orchestrate the Generation of DNA Breaks to Promote Colitis Cancer Initiation

Area of Science:

• Oncology
• Gastroenterology
• Molecular Biology

Background:

• Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is a known risk factor for colorectal cancer (CRC).
• Understanding the molecular mechanisms linking IBD and CRC is crucial for developing effective prevention and treatment strategies.

Purpose of the Study:

• To investigate the roles of topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2) in the development of CRC associated with IBD.
• To identify potential therapeutic targets for inflammation-driven colorectal cancer.

Main Methods:

• Utilized mouse models of IBD and CRC, employing pharmacological interventions, gene knockout, and knock-in approaches.
• Analyzed key pathological markers, including DNA breaks (DSBs), inflammation, and neoplastic scores, using immunohistochemical assays.
• Examined the expression and activity of TOP2 and NOS2 in disease models and human patient samples.

Main Results:

• Accumulation of DNA double-strand breaks (DSBs) and increased levels of TOP2 and NOS2 were observed in colon tissues from IBD and CRC models, as well as in CD patients.
• Genetic deletion of NOS2 or TOP2β, and pharmacological inhibition of TOP2 or NO scavenging, reduced DSB formation and disease severity.
• Inhibition of NOS2 or TOP2 activity decreased tumor burden in mice, with DSBs and tumors predominantly found in the distal colon, consistent with human CRC distribution.

Conclusions:

• TOP2 and NOS2 act cooperatively to drive DNA double-strand breaks in the context of inflammation-associated CRC.
• Targeting the interplay between TOP2 and NOS2 presents a promising therapeutic strategy for preventing and treating colorectal cancer in IBD patients.