Department of Emergency Medicine, Health Sciences Center, Stony Brook University, Stony Brook, NY, USA.
Department of Dermatology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Oncogene. 2014 Jan 9;33(2):225-35. doi: 10.1038/onc.2012.563. Epub 2013 Jan 14.
E-cadherin, a cell-cell adhesion glycoprotein, is frequently downregulated with tumorigenic progression. The extracellular domain of E-cadherin is cleaved by proteases to generate a soluble ectodomain fragment, termed sEcad, which is elevated in the urine or serum of cancer patients. In this study, we explored the functional role of sEcad in the progression of skin squamous cell carcinomas (SCCs). We found that full-length E-cadherin expression was decreased and sEcad increased in human clinical tumor samples as well as in ultraviolet (UV)-induced SCCs in mice. Interestingly, sEcad associated with members of the human epidermal growth factor receptor (HER) and insulin-like growth factor-1 (IGF-1R) family of receptors in human and UV-induced mouse tumors. Moreover, in both E-cadherin-positive (E-cadherin(+)) and -negative (E-cadherin(-)) cells in vitro, sEcad activated downstream mitogen-activated protein (MAP) kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling and enhanced tumor growth, motility and invasion, the latter via activation of matrix metalloproteinase-2 (MMP-2) and MMP-9. To this end, HER, PI3K or MEK inhibitors suppressed sEcad's tumorigenic effects, including proliferation, migration and invasion. Taken together, our data suggest that sEcad contributes to skin carcinogenesis via association with the HER/IGF-1R-family of receptors and subsequent activation of the MAPK and PI3K/Akt/mTOR pathways, thereby implicating sEcad as a putative therapeutic target in cutaneous SCCs.
E-钙黏蛋白是一种细胞间黏附糖蛋白，随着肿瘤发生的进展常被下调。E-钙黏蛋白的细胞外结构域被蛋白酶切割，产生一种可溶性的细胞外结构域片段，称为 sEcad，其在癌症患者的尿液或血清中升高。在这项研究中，我们探讨了 sEcad 在皮肤鳞状细胞癌（SCCs）进展中的功能作用。我们发现全长 E-钙黏蛋白的表达在人临床肿瘤样本以及小鼠紫外线（UV）诱导的 SCCs 中降低，而 sEcad 则增加。有趣的是，sEcad 与人表皮生长因子受体（HER）和胰岛素样生长因子-1（IGF-1R）家族成员在人及 UV 诱导的小鼠肿瘤中结合。此外，在体外的 E-钙黏蛋白阳性（E-cadherin(+)）和阴性（E-cadherin(-)）细胞中，sEcad 均激活下游丝裂原激活蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，并增强肿瘤生长、运动和侵袭能力，后者是通过激活基质金属蛋白酶-2（MMP-2）和 MMP-9。为此，HER、PI3K 或 MEK 抑制剂抑制了 sEcad 的致瘤作用，包括增殖、迁移和侵袭。综上所述，我们的数据表明，sEcad 通过与 HER/IGF-1R 家族成员结合并随后激活 MAPK 和 PI3K/Akt/mTOR 通路，促进皮肤癌变，提示 sEcad 可能是皮肤 SCC 的一个潜在治疗靶点。
