The transforming growth factor (TGF) βs are multifunctional polypeptide growth factors with diverse biological effects, including inhibition of epithelial cell proliferation both in vitro and in vivo. To investigate the possible role of TGFβ1 in the regulation of papillomavirus infection and papillomavirus-associated transformation, we compared the response to TGFβ1 of normal keratinocytes, human papillomavirus, type 16 (HPV 16)-positive-immortalized keratinocytes (nontumorigenic), and HPV 16-positive cervical carcinoma cells (tumorigenic) with respect to DNA synthesis and protooncogene expression. All HPV 16-immortalized cell lines were nearly as inhibited by TGFβ1 as normal keratinocytes, whereas two cervical carcinoma cell lines (Caski and Siha) were refractory to growth inhibition by TGFβ1. Cell surface receptors for TGFβ1 were present on both normal and carcinoma cell lines. In all cases, growth inhibition by TGFβ1 was accompanied by suppression of Steady-state levels of c-myc mRNA. In contrast, TGFβ1 induced the expression of c-jun mRNA transcripts in normal, immortalized, and tumorigenic cells. We also studied the effect of TGFβ1 on HPV 16 mRNA expression. Steady-state levels of HPV 16 mRNA transcripts were suppressed by TGFβ1 in the nontumorigenic HPK cells but were unaffected in the tumorigenic lines. These findings suggest that TGFβ1 may be an in vivo modulator of HPV infection and that loss of responsiveness to this growth inhibitory signal may be involved in HPV-associated malignant transformation.
This work was supported by USPHS Grants CA46617 (L. B.) and HD24455 (P. G.) and Deutsche Forschungsgemeinschaft Du 162/1-1 (M.D.).