Human Papilloma Virus E6 Protein Enhances Cd55 Expression on Cervical Cancer Cell Surface which Promotes Radio-Resistance and Cancer Aggressiveness

Abstract

Accumulating evidences indicate that sub-population of cells resided in tumor are responsible for the resistance to cancer therapy and recurrence. Identification and characterization of these sub-population cells is important to enhance the response for cancer treatment. However, the identity of such cells resided in cervical cancer has not yet been clearly defined due to limited clinical materials. In our present study, we isolated sphere forming cells from primary cervical tumor tissues which exhibited self renewal ability. Higher expression of “stemness” genes including Bmi-1, Nanog and Oct-4 have been detected in sphere cells as compared with their attached cells counterpart. Gene expression profiling identified a cell surface marker CD55 was up-regulated in primary cervical cancer sphere cells. CD55 is a membrane-bound complement regulatory protein (mCRPs) which is overexpressed in tumor cells. Enhanced expression of CD55 protects tumor cells to escape from complement attack. In cervical cancer cell lines, abundant CD55(+) population was detected in a panel of Human Papilloma Virus (HPV) positive cervical cancer cell lines while limited amount of CD55(+) cells were found in HPV-negative cells cervical cancer cell line C33A and normal cervical epithelial cell line NC104. By flow cytometry, CD55(+) cells isolated from C33A exhibited significant sphere-forming ability than CD55(-) cells. Functional characterization on these cells revealed that CD55(+) cells showed enhanced in vitro tumorigenicity, cell migration and radio-resistance than CD55(-) cells. Notably, ectopic expression of HPV-E6 enriched CD55(+) populations in C33A as well as NC104 cells suggesting that expression of HPV-E6 protein might induce the enrichment of CD55(+) population in HPV-negative cells. Our data suggested that HPV-E6 protein expression enriches CD55(+) population in cervical cancer. CD55(+) population plays an important role in the contribution of radio-resistance and tumor progression in cervical cancer cells. Targeting CD55 by siRNA or specific anti- CD55 antibody may provide new insight for the establishment of novel strategies and effective therapies for cervical cancer.