title: Expression of endothelins and their receptors in nonmelanoma skin cancers.
abstract: BACKGROUND
  Endothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking.
  
  
  OBJECTIVE
  This study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes.
  
  
  METHODS
  Quantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, -2, and -3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time.
  
  
  RESULTS
  ET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowen's disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival.
  
  
  CONCLUSIONS
  The endothelin signaling pathway, especially ET-1, is activated in basal keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors.
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liren
authors.initials: L
authors.lastname: Tang
authors.forename: Mingwan
authors.initials: M
authors.lastname: Su
authors.forename: Daniel
authors.initials: D
authors.lastname: Eisen
authors.forename: David
authors.initials: D
authors.lastname: Zloty
authors.forename: Lawrence
authors.initials: L
authors.lastname: Warshawski
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001913:Bowen's Disease / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics; D019333:Endothelin-2 / Q000235:genetics; D016232:Endothelins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007642:Keratosis / Q000378:metabolism; D017492:Keratosis, Seborrheic / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D019332:Endothelin-1; D019333:Endothelin-2; D016232:Endothelins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin