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首页> 外文期刊>Oncogene >Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor
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Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

机译：胃泌素释放肽在头颈部鳞状细胞中的致丝分裂作用是由表皮生长因子受体的激活介导的

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Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF- and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.
机译：头颈部鳞状细胞癌（HNSCC）的特征在于表皮生长因子受体（EGFR）的上调，其中EGFR作为潜在的治疗靶点。我们以前曾报道过，在HNSCC癌变的早期，胃泌素释放肽/胃泌素释放肽受体（GRP / GRPR）自分泌生长途径被激活。在本研究中，我们研究了GRP / GRPR在HNSCC增殖中激活EGFR的机制。在表达高水平的GRPR和EGFR的HNSCC细胞中，我们发现GRP诱导EGFR的快速磷酸化以及p44 / 42-MAPK激活。使用几种EGFR特异性酪氨酸激酶抑制剂和衍生自EGFR基因敲除小鼠的细胞，我们证明了GRP诱导的p44 / 42-MAPK激活取决于EGFR激活。进一步的研究表明，基质金属蛋白酶对转化生长因子-α（TGF-）的切割介导了GRP诱导的MAPK活化。此外，在特异性抑制EGFR或MEK后，GRP刺激的HNSCC增殖被消除，GRP未能刺激EGFR缺陷细胞的增殖。这些结果暗示在HNSCC中GRP的促有丝分裂作用由TGF-的细胞外释放介导，并且需要激活EGFR依赖性MEK / MAPK依赖性途径。

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