Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis
Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis
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DOI：
10.1007/s00418-012-0981-9
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发表时间：
2012-10-01
影响因子：
2.3
通讯作者：
Raso, E.
中科院分区：
文献类型：
--
作者：
Krenacs, T.;Kiszner, G.;Raso, E.
已知180 kDa跨膜胶原XVII将未分化的角质形成细胞锚在半桥粒中的基底膜上，同时组成性地脱落120 kDa胞外域。针对胶原蛋白XVII的遗传突变或自身抗体会导致起泡性皮肤病。胶原蛋白XVII在成熟角质形成细胞中下调，但在皮肤癌中重新表达。通过最近检测胶原XVII在黑素细胞增生，在这里，我们测试了它的表达在良性和恶性黑素细胞肿瘤使用胞内和胞外域选择性抗体。我们发现全长胶原蛋白XVII蛋白在增殖组织黑素细胞，基底角质形成细胞和鳞状细胞癌，而休息黑素细胞呈阴性。此外，仅在62/79个原发性和15/18个转移性黑素瘤、8/9个黑素瘤细胞系、HT 199转移性黑素瘤异种移植物和8/63个发育不良痣中的非典型巢中检测到细胞残留60 kDa胞内结构域。其余19例痣（普通痣、蓝痣和Spitz痣）均为阴性。与胞外域缺陷一致，COL 17 A1基因测序显示胞外域编码区存在畸变，包括点突变。胶原XVII免疫反应染色的梭形细胞黑色素瘤，显示部分重叠的配置文件与S100 B，黑色素A和HMB 45。它集中在垂直黑色素瘤前沿，并与侵袭性表型统计学相关。靶向胶原XVII胞内域的胞外aa 507 -529末端的抗体促进细胞凋亡和细胞粘附，同时抑制HT 199细胞的增殖。这些结果表明，胶原蛋白XVII胞内域在黑素细胞肿瘤中的积累与恶性转化相关，是恶性肿瘤的潜在标志物和抗体诱导的黑色素瘤细胞凋亡的靶点。
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.