Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes
Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes
复制标题
DOI：
10.1096/fj.201601138rr
复制
发表时间：
2017-08-01
期刊：
影响因子：
4.8
通讯作者：
Mahoney, My G.
中科院分区：
文献类型：
--
作者：
Overmiller, Andrew M.;Pierluissi, Jennifer A.;Mahoney, My G.
细胞外囊泡（EV）是纳米级膜衍生的囊泡，其充当携带脂质、蛋白质和遗传物质的细胞间信使。大量证据表明，由肿瘤细胞分泌到血液和其他体液中的癌源性EV在调节肿瘤微环境和影响癌症发病机制方面起着关键作用。在这里，我们首次证明鳞状细胞癌（SCC）EV富含桥粒芯糖蛋白2（Dsg 2）的C-末端片段，桥粒钙粘蛋白通常在恶性肿瘤中过表达。Dsg 2的过表达增加EV释放和促有丝分裂的内容，包括表皮生长因子受体和c-Src。用基质金属蛋白酶抑制剂GM 6001抑制Dsg 2的胞外结构域脱落导致全长Dsg 2在EV中积累并减少EV释放。当与表达Dsg 2/绿色荧光蛋白的SCC细胞共培养时，通过荧光激活细胞分选分析在CD 90（+）成纤维细胞中检测到绿色荧光蛋白信号。此外，SCC EV激活Erk 1/2和Akt信号传导并增强成纤维细胞增殖。在体内，Dsg 2在头颈部SCC中高度上调，并且从SCC患者血清中分离的EV富含Dsg 2 C末端片段和表皮生长因子受体。这项研究定义了一种机制，通过这种机制，癌细胞中的Dsg 2表达可以调节肿瘤微环境，这是肿瘤进展的关键步骤。
Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor micro-environment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90(+) fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. In vivo, Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.