Expression of endothelins and their receptors in nonmelanoma skin cancers

Yi Zhang, Liren Tang, Mingwan Su, Daniel B Eisen, David Zloty, Lawrence Warshawski, Youwen Zhou

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Objectives: 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. Conclusion: The endothelin signaling pathway, especially ET-1, is activated in basoloid 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.

Original languageEnglish (US)
Pages (from-to)269-276
Number of pages8
JournalJournal of Cutaneous Medicine and Surgery
Volume10
Issue number6
DOIs
StatePublished - Nov 2006

Fingerprint

Endothelin Receptors
Endothelins
Skin Neoplasms
Keratinocytes
Seborrheic Keratosis
Cell Survival
Basal Cell Carcinoma
Endothelin-1
Peptides
Neoplasms
Lentigo
RNA
Bowen's Disease
Actinic Keratosis
Growth Inhibitors
Skin
Growth
Skin Tests
Bromides
Genes

ASJC Scopus subject areas

  • Dermatology
  • Surgery

Cite this

Expression of endothelins and their receptors in nonmelanoma skin cancers. / Zhang, Yi; Tang, Liren; Su, Mingwan; Eisen, Daniel B; Zloty, David; Warshawski, Lawrence; Zhou, Youwen.

In: Journal of Cutaneous Medicine and Surgery, Vol. 10, No. 6, 11.2006, p. 269-276.

Research output: Contribution to journalArticle

Zhang, Yi ; Tang, Liren ; Su, Mingwan ; Eisen, Daniel B ; Zloty, David ; Warshawski, Lawrence ; Zhou, Youwen. / Expression of endothelins and their receptors in nonmelanoma skin cancers. In: Journal of Cutaneous Medicine and Surgery. 2006 ; Vol. 10, No. 6. pp. 269-276.
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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. Objectives: 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. Conclusion: The endothelin signaling pathway, especially ET-1, is activated in basoloid 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.",
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