The hemidesmosomal protein BP180 (collagen XVII) in skin cancer and inflammation Public Deposited

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  • March 22, 2019
Creator
  • HWANG, BIN-JIN
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • BP180, also known as collagen XVII, is a transmembrane glycoprotein located in the hemidesmosome of basal keratinocytes, and functions as a key cell-matrix adhesion molecule. Loss of BP180 function in human disease leads to subepidermal blistering, and can occur by either autoantibody production (bullous pemphigoid) or inherited mutations in the BP180 gene COL17A1 (junctional epidermolysis bullosa). However, its other biological functions and involvement in different pathological conditions are unknown. To uncover new functions of BP180, we generated a novel BP180 dysfunctional mouse strain lacking the NC16A domain of BP180 (termed ΔNC16A). We found that ΔNC16A mice developed a proinflammatory microenvironment in the skin accompanied by an influx of immune cells, including mast cells and MDSCs. ΔNC16A mice show spontaneous skin inflammation accompanied by TSLP-dependent itch. When tested in the B16 mouse melanoma models, ΔNC16A mice showed significantly increased melanoma progression. NC16A deletion in the skin or epidermis was sufficient to promote skin inflammation and tumor progression, demonstrating that BP180 dysfunction in basal keratinocytes is responsible for the proinflammatory microenvironment and increased tumor progression. Mast cell-deficient ΔNC16A mice had drastically reduced MDSCs in the skin and developed significantly reduced melanoma. Mast cell reconstitution restored the skin infiltration of MDSCs and increased melanoma progression in mast cell-deficient ΔNC16A mice. More importantly, MDSC depletion significantly reduced the tumor progression in mast cell-sufficient ΔNC16A mice. These findings provide the first evidence suggesting that BP180 in basal keratinocytes, as a hemidesmosomal cell-cell matrix adhesion protein, plays a vital role in skin inflammation and melanoma progression.
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Advisor
  • Ting, Jenny P.-Y.
  • Liu, Zhi
  • Williams, Scott
  • Wan, Yisong
  • Su, Maureen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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