Investigation of the role of IKK-related kinases in colitis-associated cancer

Abstract

Colitis-associated cancer (CAC) is a serious consequence of persistent colonic inflammation, predominantly occurring in individuals with prolonged ulcerative colitis. The molecular processes underlying CAC include chronic inflammation, immunological dysfunction, and abnormal activation of oncogenic signaling pathways. IKK-related kinases are pivotal regulators of immunological signaling, inflammation, and cancer. Nonetheless, their precise functions in CAC remain inadequately understood. In this study, to understand the effects of IKK-kinase inhibition on the onset and the development of CAC, three experimental setups that mimic acute, chronic and cancer phases of the disease were employed by AOM/DSS induced CRC mouse model. Clinical and histological activity scoring were conducted across acute, chronic, and cancer phases to assess the effect of pharmacological inhibition of IKK-related kinases on disease severity, tumor burden, and mouse survivals. Furthermore, we examined cytokine and chemokine profiles, immune cell infiltration, and oxidative stress markers to ascertain the role of these kinases in the inflammatory tumor microenvironment. Finally, to establish the clinical relevance of our findings, publicly available single-cell RNA sequencing data of ulcerative colitis patients were analyzed to identify potential parallels in human disease. It has been demonstrated that the modulation of immune response and the initiation and development of tumors in the CAC are significantly impacted by IKK-related kinase activity.