title: Notch signaling is significantly suppressed in basal cell carcinomas and activation induces basal cell carcinoma cell apoptosis.
abstract: A subset of basal cell carcinomas (BCCs) are directly derived from hair follicles (HFs). In some respects, HFs can be defined as 'ordered' skin appendage growths, while BCCs can be regarded as 'disordered' skin appendage growths. The aim of the present study was to examine HFs and BCCs to define the expression of common and unique signaling pathways in each skin appendage. Human nodular BCCs, along with HFs and non‑follicular skin epithelium from normal individuals, were examined using microarrays, qPCR, and immunohistochemistry. Subsequently, BCC cells and root sheath keratinocyte cells from HFs were cultured and treated with Notch signaling peptide Jagged1 (JAG1). Gene expression, protein levels, and cell apoptosis susceptibility were assessed using qPCR, immunoblotting, and flow cytometry, respectively. Specific molecular mechanisms were found to be involved in the process of cell self‑renewal in the HFs and BCCs, including Notch and Hedgehog signaling pathways. However, several key Notch signaling factors showed significant differential expression in BCCs compared with HFs. Stimulating Notch signaling with JAG1 induced apoptosis of BCC cells by increasing Fas ligand expression and downstream caspase-8 activation. The present study showed that Notch signaling pathway activity is suppressed in BCCs, and is highly expressed in HFs. Elements of the Notch pathway could, therefore, represent targets for the treatment of BCCs and potentially in hair follicle engineering.
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Feng-Tao
authors.initials: FT
authors.lastname: Shi
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Zloty
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Eddy
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Noushin
authors.initials: N
authors.lastname: Akhoundsadegh
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Gigi
authors.initials: G
authors.lastname: Leung
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Carr
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McElwee
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016000:Cluster Analysis; D053222:Fas Ligand Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000072100:Jagged-1 Protein / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D051880:Receptors, Notch / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D053222:Fas Ligand Protein; D000072100:Jagged-1 Protein; D051880:Receptors, Notch