Differential response of nontumorigenic and tumorigenic human papillomavirus type 16-positive epithelial cells to transforming growth factor beta 1.
The transforming growth factor (TGF) beta s 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 TGF beta 1 in the regulation of papillomavirus infection and papillomavirus-associated transformation, we compared the response to TGF beta 1 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 TGF beta 1 as normal keratinocytes, whereas two cervical carcinoma cell lines (Caski and Siha) were refractory to growth inhibition by TGF beta 1. Cell surface receptors for TGF beta 1 were present on both normal and carcinoma cell lines. In all cases, growth inhibition by TGF beta 1 was accompanied by suppression of Steady-state levels of c-myc mRNA. In contrast, TGF beta 1 induced the expression of c-jun mRNA transcripts in normal, immortalized, and tumorigenic cells. We also studied the effect of TGF beta 1 on HPV 16 mRNA expression. Steady-state levels of HPV 16 mRNA transcripts were suppressed by TGF beta 1 in the nontumorigenic HPK cells but were unaffected in the tumorigenic lines. These findings suggest that TGF beta 1 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.
Braun
L
L
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912.
Dürst
M
M
Mikumo
R
R
Gruppuso
P
P
D002455:Cell Division / Q000187:drug effects; D002584:Cervix Uteri / Q000382:microbiology / Q000473:pathology; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics; D004848:Epithelium / Q000382:microbiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000382:microbiology; D027383:Papillomaviridae / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000627:therapeutic use*; D014412:Tumor Virus Infections / Q000628:therapy*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA