Alterations in Cytokine/Antioncogene Expression in Skin Lesions Caused by "Low-Risk" Types of Human Papillomaviruses

Abstract

Even though the "low-risk" human papillomavirus (HPV) diseases, such as condyloma acuminatum, rarely progress to malignancy, their high incidence evidences the need for a better understanding of molecular interactions between these viruses and the epithelium. Our study examined the contribution of altered expression of certain cytokines and antioncogenes to the hyperproliferative properties of HPV-related skin lesions. The "low-risk" human papillomavirus types (HPV 6 or 11) were determined by in situ hybridization and PCR amplification followed by direct sequencing using consensus primers from the highly conserved L1 region in six different condylomas. mRNA levels of certain cytokines (e.g., TGF-beta 1, IFN-beta), tumor suppressor genes (RB, p53), c-myc, epidermal growth factor receptor, and cdc2 kinase were measured by RT/PCR. A characteristic change in mRNA levels of those genes was found in condylomas compared to that of the expression levels of uninfected skin. Western blot experiments demonstrated a higher proportion of the hyperphosphorylated form of RB protein and a higher level of cdc2 kinase and c-myc, but low p53 and TGF-beta 1 levels in condylomas. These data reflect a higher proliferative state of those condylomas compared to the normal skin, suggesting a direct or indirect involvement of "low-risk" HPVs in interaction with the cellular cytokine/antioncogene system providing growth advantage to those infected cells.