COX2: A Prognostic Inflammogenic Marker Drives Cervical Carcinogenesis in Vivo through the NFκB/IAP/p53Axis

Abstract Cycloxygenase 2, a prostaglandin synthesizing enzyme, is a key player in inflammation-induced vasculogenesis that enables tumor growth. This study explores the central role of COX2 and its relative prosurvival proteins in evoking inflammatory events during the development of an in vivo cervical cancer model upon chronic treatment with 3-methylcholanthrene (3MC; a chemical carcinogen) in virgin-female Swiss albino mice. Chronic painting of the mouse cervix with 3MC solution triggered the persistent expression and activity of COX2, eventuating the overexpression of major prosurvival molecules (NFκB, XIAP, survivin, GM-CSF1) and proliferative antigens (Ki67, PCNA). COX2-arbitrated prosurvival signaling subsequently deranged the expression profiles of tumor suppressor proteins (p53/acetyl-p53, p21, Rb) within the cervix. COX2 mediated molecular alterations successively surged leukocyte influx within the cervix, catering to localized inflammation that gradually distorted its tissue architecture. Cervical carcinogenesis was further braced by higher levels of systemic ROS and RNS, escalated iNOS activity and compromised antioxidant enzyme capacities, which were accompanied by splenomegaly. Additionally, circulation of blood leucocytes with damaged DNA throughout the mouse body envisaged the impact of cervix-limited inflammation on mouse physiology. Conclusively, the present study deciphered the role of COX2 in affecting NFκB/IAP/p53 functions in sequestering the contributors of localized and systemic inflammogenesis to propel 3MC-mediated cervical carcinogenesis in vivo.