Hepatocyte growth factor and c-Met in cervical intraepithelial neoplasia: overexpression of proteins associated with oncogenic human papillomavirus and human immunodeficiency virus.

Abstract

High prevalence of squamous cervical intraepithelial neoplasia (CIN) linked to oncogenic human papillomavirus (HPV) exits in HIV-infected women. Hepatocyte growth factor (HGF) and its receptor, c-Met, promote cell proliferation and are involved in tumor progression. Nothing is yet known about their expression in low- and high-grade CIN. Therefore, the expression, localization, and behavior of HGF and c-Met in normal and dysplastic cervical epithelium were investigated. We studied normal cervical mucosa from 10 healthy women, and low- and high-grade cervical lesions, uninfected (condyloma acuminata) or infected with oncogenic HPVs, from 40 HIV-negative and 48 HIV-positive women, using in situ molecular techniques, immunocytochemistry and morphoquantitative methods. In 154 oncogenic HPV-infected CIN encountered in biopsy samples, the total number of epithelial cell layers increased significantly during lesion progression. This number was significantly higher in HIV-positive than in HIV-negative women for CIN1 and CIN2 (P < 0.025 to P < 0.01). In HIV-negative women, the number and percentage of HGF and c-Met immunostained cell layers, and the intensity of immunostaining were enhanced in oncogenic HPV-infected lesions as compared with normal mucosa and condyloma acuminata. The latter parameters were significantly higher in tissues of HIV-positive women (oncogenic HPV-infected CIN1 and CIN2, normal-appearing mucosa contiguous to CIN, condyloma acuminata) than in the corresponding tissues of HIV-negative women (P < 0.025 to P < 0.0001). Overexpression of HGF/c-Met complex strongly correlates with oncogenic HPV and HIV infection. This overexpressed complex may stimulate cell proliferation in condyloma acuminata and participate in tumor progression in oncogenic HPV-infected lesions.