The autonomous growth of human papillomavirus type 16-immortalized keratinocytes is related to the endothelin-1 autocrine loop.
Some human papillomaviruses (HPVs) such as HPV type 16 (HPV16) and HPV18 are involved in cervical carcinoma, and they can immortalize and transform keratinocytes. Endothelin-1 (ET-1) is produced in keratinocytes and has been shown to act through ETA receptors as an autocrine growth factor for keratinocytes. This study examines whether HPV16 alters the ET-1-mediated autocrine loop in human keratinocytes, providing a selective growth advantage for transformed cells. ET-1 is released in similar amounts from normal and HPV-transfected keratinocytes. All HPV-transfected cell lines express high-affinity ETA receptors. A two-fold increase in ET-1 binding sites is present in HPV16-immortalized keratinocytes, and this effect seems to be linked to the overexpression of mRNA for this receptor rather than to differences in the surface/internalized ratio of the receptors. ET-1 induces significant increases in [3H]thymidine incorporation and cell proliferation. Furthermore, HPV-transfected keratinocytes can proliferate in the absence of any growth factor added to the growth medium, and the ETA receptor antagonist BQ123 prevents this proliferation. These data suggest a new mechanism in the growth control of HPV-transformed cells mediated by the upregulation of ET-1 autocrine loop.
Venuti
A
A
Laboratory of Virology, Regina Elena Institute for Cancer Research, Rome, Italy. venuti@crs.ifo.it
Marcante
M L
ML
Flamini
S
S
Di Castro
V
V
Bagnato
A
A
D002455:Cell Division; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002648:Child; D019332:Endothelin-1 / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000821:virology; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000502:physiology; D027383:Papillomaviridae / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins
C068651:E6 protein, Human papillomavirus type 16; D019332:Endothelin-1; D008934:Mitogens; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16