Oncoproteins E6/E7 of the Human Papillomavirus Types 16 & 18 Cooperate in Modulating Oncogenes and Tumor Suppressor Proteins in Colorectal Cancer

Abstract

Background This study presents a novel analysis of the oncogenes and tumor suppressor proteins directly modulated by E6/E7 of high-risk HPV types 16 and 18, in two mutational cell models of colorectal cancer (CRC).Methods Two distinct mutational cell models of colorectal cancer, HCT 116 (KRAS mutant) & HT-29 (TP53 mutant) were transfected with E6/E7 of HPV16 and HPV18, individually and in combination (co-transfection), via lipofection. Further, we utilized a liquid chromatography mass spectrometry (LC-MS/MS) approach to analyze and compare the proteomes of KRAS mutant HCT 116 and TP53 mutant HT-29 cell models of CRC, expressing E6/E7 of HPVs type 16 and 18, both, individually and in combination.Results We generated six stably transfected cell lines, namely, HCT 116 HPV16+, HCT 116 HPV18+, HCT 116 HPV16+/18+, HT-29 HPV16+, HT-29 HPV18+, HT-29 HPV16+/18+. Our proteomics data revealed a significantly higher, HPV-induced, modulation of oncogenes and tumor suppressor proteins in the TP53 mutant model of CRC, as compared to the KRAS mutant cell model (p ≤ 0.01). Less than 1% of the genes were found to be commonly modulated by HPV, between the two models of CRC. In addition, we report that HT-29 cells, expressing E6/E7 of both HPVs 16 and 18, significantly reduced the downregulation of oncogenes as compared to cells expressing E6/E7 of either HPV16 or HPV18 individually (p-value is ≤ 0.00001).Conclusion Our data imply that coinfections with the two most frequently observed high-risk HPV types worldwide, leads to the sustenance of a pro-oncogenic environment in CRC; that is suggestive of the cooperative role of the viruses in inflicting cancer. Further, HPV modulates different sets of oncogenes/tumor suppressor proteins in CRC models of varying mutational backgrounds, thus highlighting the importance of personalized therapies for diseases with mutational heterogeneities.