Co-Presence and Cooperation of High-Risk Human Papillomaviruses and Epstein-Barr Virus in Colorectal Cancer

Abstract

The Human Papillomavirus (HPV) and Epstein-Barr Virus (EBV) are potent oncoviruses involved in the pathogenesis of various cancers like colorectal cancer. Further the cooperation between high risk (HR) types of HPV as well as the cooperation between HPV and EBV has been implied in many previous studies. Here we aim to explore the cooperative role played by these oncoviruses through a multifaceted analysis based on colorectal cancer patient cohorts as well as assessment of colorectal cancer cell models. Further we use a holistic systems biology approach to evaluate the proteomes of cell models depicting HPV infections and co-infections, thus providing a well-rounded and comprehensive interpretation of the cellular, molecular and genetic aspects of oncoviral modulated colorectal cancer. Our study is the first of its kind to report the co-presence of HR HPVs in 35% of colorectal cancer samples from Qatar where it was found to strongly correlate with advanced stage (stage 3 and 4) colorectal cancer. In addition, we report the co-presence of HPV and EBV in 17% of the samples from Qatar and 17% of the samples from Syria. Additionally, through an immunohistochemistry-based assessment we identified a significant association between the co-presence of HPV and EBV and the expression of epithelial-mesenchymal transitions (EMT) markers like epithelial protein lost in neoplasm (EPLIN), fascin and vimentin. In addition, through an in-vitro analysis in colorectal cancer cell models, we show that the cooperative role of HPV16 and HPV18 significantly increases cellular proliferation and modulates the expression of proteins implied in EMT. Lastly, we compared and contrasted the oncogenes and tumor suppressor proteins directly modulated by single and double HPV-infections in colorectal cancer cell models of varying mutational backgrounds. Consequently, we report that the HPV16 and HPV 18 cooperate in maintaining an upregulation of oncogenes in colorectal cancer.