Chih-Li Lin

Type

Text

Type

Dissertation

Advisor

Chen, Jiang | Mao, Cungui. | Hannun, Yusuf | Obeid, Lina | Shroyer, Kenneth | Clark, Richard.

Date

2017-08-01

Keywords

Alkaline ceramidase | Molecular biology | Biochemistry | Alopecia | Ceramide | Skin cancer | Sphingolipid | Stem cell

Department

Department of Molecular and Cellular Biology.

Language

en_US

Source

This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree

Identifier

http://hdl.handle.net/11401/78348

Publisher

The Graduate School, Stony Brook University: Stony Brook, NY.

Format

application/pdf

Abstract

Ceramides and their metabolites are important for the homeostasis of the epidermis, but much remains unknown about what are the roles of specific pathways of ceramide metabolism in skin biology. Squamous cell carcinoma (SCC), the most aggressive non-melanoma skin cancer (NMSC), is the second most common form of malignancy in humans. The SCC arises from the malignancy of epidermal keratinocytes, the major cell type of the epidermis. A tight control of the proliferation and differentiation of epidermal keratinocytes (EK) is key to the homeostasis of the mammalian epidermis and its appendages. Alkaline ceramidase 1 (Acer1) is a skin-specific enzyme that plays an important role in regulating the proliferation and differentiation of epidermal keratinocytes by controlling the hydrolysis of specific ceramide species. With a mouse model deficient in the alkaline ceramidase (Acer1) gene, we demonstrate that Acer1 plays a key role in the homeostasis of the epidermis and skin carcinogenesis by controlling the metabolism of ceramides. Loss of Acer1 elevated the levels of various ceramides and sphingoid bases in the skin and caused progressive hair loss in mice. Mechanistic studies revealed that loss of Acer1 widened follicular infundibulum and caused progressive loss of hair follicle cells (HFSC) due to reduced survival and stemness. Loss of Acer protected mice from cutaneous two-stage chemical carcinogenesis and UVB-irradiation carcinogenesis. These findings suggest that Acer1 plays a key role in maintaining the homeostasis of the HFSC and thereby the hair follicle structure and function by regulating the metabolism of ceramides in the epidermis. Moreover, our data suggest a novel role of Acer1 in regulating skin tumorigenesis by directly controlling the number of tumor-initiating cells. | 123 pages

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