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首页> 外文期刊>Oncogene >Soluble E-cadherin: a critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling
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Soluble E-cadherin: a critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling

机译:可溶性E-钙粘蛋白:调节受体酪氨酸激酶,MAPK和PI3K / Akt / mTOR信号的关键癌基因

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摘要

E-cadherin, a cell鈥揷ell 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~(鈭?/sup>) 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鈥檚 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.
机译:E-钙粘着蛋白是一种细胞脱落的粘附糖蛋白,通常会随着致瘤进展而下调。 E-钙粘蛋白的胞外结构域被蛋白酶切割,产生可溶的胞外域片段,称为sEcad,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(SCC)进展中的功能作用。我们发现,在人类临床肿瘤样品以及小鼠的紫外线(UV)诱导的SCC中,全长E-钙粘蛋白的表达降低而sEcad升高。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)家族的成员相关,它们是人类和紫外线诱发的小鼠肿瘤中的受体。此外,在体外E-钙粘蛋白阳性(E-cadherin〜(+))和-阴性(E-cadherin_(s?/ sup>))细胞中,sEcad都激活下游的促分裂原活化蛋白(MAP)。激酶(MAPK)和磷脂酰肌醇3-激酶(PI3K)/ Akt /哺乳动物的雷帕霉素靶标(mTOR)信号转导并增强了肿瘤的生长,运动和侵袭,后者通过激活基质金属蛋白酶2(MMP-2)和MMP-9激活为此,HER,PI3K或MEK抑制剂可抑制sEcad的致瘤作用,包括增殖,迁移和侵袭我们的数据表明,sEcad通过与HER / IGF-1R受体家族的结合而促进皮肤癌变。以及随后激活MAPK和PI3K / Akt / mTOR通路,从而暗示sEcad作为皮肤SCC的假定治疗靶标。

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