Systemic Chromosome Instability Resulted in Colonic Transcriptomic Changes in Metabolic, Proliferation, and Stem Cell Regulators in Sgo1(-/+) Mice

摘要

Colon cancer is the second most lethal cancer and is predicted to claim 49,700 lives in the United States this year. Chromosome instability (CIN) is observed in 80% to 90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. To investigate the impact of CIN on colon cancer development, we developed shugoshin-1 (Sgo1) haploinsufficient (-/+) mice, an animal model focusing on mitotic error-induced CIN. In this study, we analyzed signature changes in the colonic transcriptome of Sgo1(-/+) mice to examine the molecular events underlying the altered carcinogenesis profiles in Sgo1(-/+) mice. We performed next-generation sequencing of normal-looking colonic mucosal tissue from mice treated with the carcinogen azoxymethane after 24 weeks. Transcriptome profiling revealed 349 hits with a 2-fold expression difference threshold (217 upregulated genes, 132 downregulated genes, P < 0.05). Pathway analyses indicated that the Sgo1-CIN tissues upregulated pathways known to be activated in colon cancer, including lipid metabolism (z score 4.47), Notch signaling (4.47), insulin signaling (3.81), and PPAR pathways (3.75), and downregulated pathways involved in immune responses including allograft rejection (6.69) and graft-versus-host disease (6.54). Notably, stem cell markers were also misregulated. Collectively, our findings demonstrate that systemic CIN results in transcriptomic changes in metabolism, proliferation, cell fate, and immune responses in the colon, which may foster a microenvironment amenable to cancer development. Therefore, therapeutic approaches focusing on these identified pathways may be valuable for colon cancer prevention and treatment. (C) 2016 AACR.