The 180 kDa transmembrane
collagen XVII is known to anchor undifferentiated keratinocytes to the basement membrane in hemidesmosomes while constitutively shedding a 120 kDa ectodomain. Inherited mutations or auto-
antibodies targeting
collagen XVII cause blistering
skin disease.
Collagen XVII is down-regulated in mature keratinocytes but re-expressed in
skin cancer. By recently detecting
collagen XVII in melanocyte
hyperplasia, here we tested its expression in benign and malignant melanocytic
tumors using endodomain and ectodomain selective
antibodies. We found the full-length
collagen XVII protein in proliferating tissue melanocytes, basal keratinocytes and
squamous cell carcinoma whereas resting melanocytes were negative. Furthermore, the cell-residual 60 kDa endodomain was exclusively detected in 62/79 primary and 15/18 metastatic
melanomas, 8/9
melanoma cell lines, HT199 metastatic
melanoma xenografts and atypical nests in 8/63
dysplastic nevi. The rest of 19
nevi including common, blue and Spitz subtypes were also negative. In line with the defective ectodomain, sequencing of COL17A1 gene revealed aberrations in the ectodomain coding region including point mutations.
Collagen XVII immunoreaction-stained spindle cell
melanomas, showed partly overlapping profiles with those of S100B,
Melan A and HMB45. It was concentrated at vertical
melanoma fronts and statistically associated with invasive phenotype. Antibody targeting the extracellular aa507-529 terminus of
collagen XVII endodomain promoted apoptosis and cell adhesion, while inhibiting proliferation in HT199 cells. These results suggest that the accumulation of
collagen XVII endodomain in melanocytic
tumors is associated with malignant transformation to be a potential marker of
malignancy and a target for antibody-induced
melanoma apoptosis.