Endothelin-2 is upregulated in basal cell carcinoma under control of Hedgehog signaling pathway.
Vasoactive peptide endothelins are a group of small peptides with diverse paracrine/autocrine actions and are reported to be involved in the pathogenesis of many human malignancies. Basal cell carcinoma (BCC) is a common malignant skin tumor that frequently has aberrant activation of the Hedgehog (HH) signaling pathway. We show here that endothelin-2 (ET-2) is overexpressed in BCC under the control of HH signaling. By real-time quantitative RT-PCR analysis, significant expression of ET-2 mRNA was observed in 19 of 20 cases (95%) compared to normal skin. In addition, inhibition of the HH signaling pathway in a mouse BCC cell line downregulated endogenous ET-2, and activation of HH signaling in mouse embryonic fibroblast upregulated endogenous ET-2. Moreover, the 3' promoter region of ET-2 gene contains the GLI-binding site and a 0.8kb downstream fragment containing GLI-binding sites activates transcription in a reporter assay. These data indicate that ET-2 is a direct target gene of HH signaling in BCC.
Tanese
Keiji
K
Department of Pathology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Fukuma
Mariko
M
Ishiko
Akira
A
Sakamoto
Michiie
M
D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics*; D019333:Endothelin-2 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics*; D000071676:Zinc Finger Protein GLI1
D019333:Endothelin-2; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D000071676:Zinc Finger Protein GLI1