Caveolin-1 expression is down-regulated in cells transformed by the human papilloma virus in a p53-dependent manner. Replacement of caveolin-1 expression suppresses HPV-mediated cell transformation

Squamous cell carcinomas of the lung and cervix arise by neoplastic transfo rmation of their respective tissue epithelia. In the case of cervical carci nomas, an increasing body of evidence implicates the human papillomavirus, HPV (types 16 and Is), as playing a pivotal role in this malignant transfor mation process. The HPV early genes E6 and E7 are known to inactivate the t umor suppressors p53 and Rb, respectively; this leads to disruption of cell cycle regulation, predisposing cells to a cancerous phenotype. However, th e role of caveolin-1 (a putative tumor suppressor) in this process remains unknown. Here, we show that caveolin-1 protein expression is consistently r educed in a panel of lung and cervical cancer derived cell lines and that t his reduction is not due to hyperactivation of p42/44 MAP kinase (a known n egative regulator of caveolin-1 transcription). Instead, we provide evidenc e that this down-regulation event is due to expression of the HPV E6 viral oncoprotein, as stable expression of E6 in NIH 3T3 cells is sufficient to d ramatically reduce caveolin-1 protein levels. Furthermore, we demonstrate t hat p53-a tumor suppressor inactivated by E6-is a positive regulator of cav eolin-1 gene transcription and protein expression. SiHa cells are derived f rom a human cervical squamous carcinoma, harbor a fully integrated copy of the HPV 16 genome (including E6), and show dramatically reduced levels of c aveolin-1 expression. We show here that adenoviral-mediated gene transfer o f the caveolin-1 cDNA to SiHa cells restores caveolin-1 protein expression and abrogates their anchorage-independent growth in soft agar. Taken togeth er, our results suggest that the HPV oncoprotein E6 down-regulates caveolin -1 via inactivation of p53 and that replacement of caveolin-1 expression ca n partially revert HPV-mediated cell transformation.