Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis
Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis
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DOI：
10.1158/1541-7786.mcr-13-0003-t
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发表时间：
2013-08-01
影响因子：
5.2
通讯作者：
Craig, Andrew W. B.
中科院分区：
文献类型：
--
作者：
Ahn, Joseph;Truesdell, Peter;Craig, Andrew W. B.
表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）中经常扩增或突变。尽管Fer蛋白酪氨酸激酶信号位于EGFR下游，但其在NSCLC肿瘤进展中的作用尚未报道。在此，Fer激酶在NSCLC肿瘤中比正常肺上皮细胞中升高。NSCLC细胞中的EGFR信号传导促进快速Fer活化并增加板状伪足的定位。与对照细胞相比，H1299肺腺癌细胞（Fer KD）中Fer的稳定沉默导致EGFR诱导的板状伪足形成受损。Fer KD NSCLC细胞显示Vav 2酪氨酸磷酸化减少，这与酪氨酸-172上的Vav 2的直接Fer介导的磷酸化相关，这先前被报道增加Vav 2的鸟嘌呤核苷酸交换因子活性。事实上，Fer KD细胞在体外表现出Rac-GTP定位于板状伪足、细胞迁移和细胞侵袭的缺陷。为了测试Fer在NSCLC进展和转移中的作用，将对照和Fer KD细胞作为皮下肿瘤在小鼠中生长。虽然Fer不是肿瘤生长所必需的，但Fer KD荷瘤小鼠的自发转移数量显著较少。结合，这些数据表明，Fer激酶在NSCLC肿瘤中升高，是重要的细胞侵袭和transferation.Implications：Fer蛋白酪氨酸激酶是一个潜在的治疗靶点在转移性肺癌。(C)2013年AACR。
Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non-small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis.Implications: Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. (C) 2013 AACR.