Erk2 but not Erk1 regulates crosstalk between Met and EGFR in squamous cell carcinoma cell lines.
Erk2 but not Erk1 regulates crosstalk between Met and EGFR in squamous cell carcinoma cell lines.
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DOI：
10.1186/s12943-015-0319-z
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发表时间：
2015-03-04
期刊：
影响因子：
37.3
通讯作者：
Ullrich A
中科院分区：
文献类型：
--
作者：
Gusenbauer S;Zanucco E;Knyazev P;Ullrich A
鳞状细胞癌（SCC）是最常见的舌癌和喉癌类型，也是常见的肺癌类型。在这项研究中，我们试图具体评估HGF/Met诱导的EGFR配体在SSC中释放的信号通路。Met原癌基因编码酪氨酸激酶受体，其通常在人类癌症中过度活化。Met激活与患者预后不良相关。几项研究揭示了Met在受体串扰中的作用，其诱导其他受体的活化或诱导它们对靶向癌症治疗的抗性。在上皮肿瘤细胞系筛选中，我们最近显示Met配体HGF阻断EGFR酪氨酸激酶，同时激活转录上调和EGFR配体双调蛋白在上清液中的积累（Oncogene 32：3846-56，2013）。在目前的工作中，我们描述了负责双调蛋白诱导的途径。双调蛋白被转录上调并释放到上清液中。我们发现，Erk 2，而不是Erk 1介导的双调蛋白上调后处理单核细胞衍生的HGF。Erk 2的siRNA敲低完全消除鳞状细胞癌中的双调蛋白释放。这些结果鉴定了Erk 2作为在源自舌、喉和肺的鳞状细胞癌细胞系中Met活化和EGFR配体上调之间的关键下游信号转导子。本文的在线版本（doi：10.1186/s12943-015-0319-z）包含补充材料，可供授权用户使用。
Squamous cell carcinoma (SCC) is the most common type of tongue and larynx cancer and a common type of lung cancer. In this study, we attempted to specifically evaluate the signaling pathway underlying HGF/Met induced EGFR ligand release in SSCs. The Met proto-oncogene encodes for a tyrosine kinase receptor which is often hyperactivated in human cancers. Met activation correlates with poor patient outcome. Several studies revealed a role of Met in receptor-crosstalk inducing either activation of other receptors, or inducing their resistance to targeted cancer treatments. In an epithelial tumor cell line screen we recently showed that the Met ligand HGF blocks the EGFR tyrosine kinase and at the same time activates transcriptional upregulation and accumulation in the supernatant of the EGFR ligand amphiregulin (Oncogene 32:3846–56, 2013). In the present work we describe the pathway responsible for the amphiregulin induction. Amphiregulin is transcriptionally upregulated and is released into the supernatant. We show that Erk2 but not Erk1 mediates amphiregulin upregulation upon treatment with monocyte derived HGF. A siRNA knockdown of Erk2 completely abolishes amphiregulin release in squamous cell carcinomas. These results identify Erk2 as the key downstream signal transducer between Met activation and EGFR ligand upregulation in squamous cell carcinoma cell lines derived from tongue, larynx and lung. The online version of this article (doi:10.1186/s12943-015-0319-z) contains supplementary material, which is available to authorized users.
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