Lasp1 promotes malignant phenotype of non-small-cell lung cancer via inducing phosphorylation of FAK-AKT pathway.
Lasp1 promotes malignant phenotype of non-small-cell lung cancer via inducing phosphorylation of FAK-AKT pathway.
复制标题
Lasp1通过诱导FAK-AKT通路磷酸化促进非小细胞肺癌恶性表型
DOI：
10.18632/oncotarget.20527
复制
发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Wang E
中科院分区：
文献类型：
--
作者：
Zhang X;Liu Y;Fan C;Wang L;Li A;Zhou H;Cai L;Miao Y;Li Q;Qiu X;Wang E
Lasp 1（LIM和SH 3结构域蛋白1）促进包括非小细胞肺癌（NSCLC）在内的多种癌症实体的肿瘤增殖和侵袭。然而，分子机制是不确定的日期。在本研究中，我们使用免疫组织化学方法发现Lasp 1表达与肿瘤大小（P=0.005）、晚期TNM分期（P=0.042）、区域淋巴结转移（P=0.034）和总生存率（P<0.001）显著相关。肺鳞癌组与肺癌组比较差异无统计学意义（P> 0.05），肺鳞癌组与肺癌组比较差异无统计学意义（P> 0.05），肺鳞癌组与肺癌组比较差异无统计学意义（P> 0.05），肺鳞癌组与肺癌组比较差异无统计学意义（P>0.05），肺鳞癌组与肺癌组比较差异无统计学意义（P>0.05）。增殖和侵袭实验表明，Lasp 1能显著促进NSCLC细胞的增殖和侵袭能力。Western blot结果显示，Lasp 1促进Cyclin A2、CyclinB 1和Snail的表达，抑制E-cadherin的表达。Lasp 1直接与FAK相互作用，促进磷酸化FAK（Tyr 397）和AKT（Ser 473）的表达。FAK抑制剂和AKT抑制剂的掺入抵消了由Lasp 1过表达诱导的Cyclin A2、CyclinB 1和Snail的表达上调，以及E-cadherin的表达下调。有趣的是，FAK信号通路的抑制减弱了AKT的磷酸化，但抑制AKT信号通路并不影响FAK的磷酸化。结论：Lasp 1通过与FAK直接结合，增强FAK（Tyr 397）和AKT（Ser 473）的磷酸化，促进NSCLC的增殖和侵袭。Lasp 1有可能成为NSCLC治疗的新靶点。
Lasp1 (LIM and SH3 domain protein 1) promotes tumor proliferation and invasion in multiple cancer entities including non-small cell lung cancer (NSCLC). However, the molecular mechanism is uncertain to date. In the present study, using immunohistochemistry, we found that Lasp1 expression was significantly correlated with tumor size (P=0.005), advanced TNM stage (P=0.042), positive regional lymph node metastasis (P=0.034) and poor overall survival (P<0.001). Similar results were seen in patients with squamous cell lung carcinoma (P=0.003 for larger tumor size, P=0.017 for advanced TNM stage, P=0.003 for positive lymph node metastasis and P<0.001 for poor overall survival) but not in patients with lung adenocarcinoma (P>0.05). Proliferation and invasion assay showed that Lasp1 dramatically promoted the ability of proliferation and invasion of NSCLC cells. Subsequent western blot results revealed that Lasp1 promoted the expression of Cyclin A2, CyclinB1, and Snail, and inhibited the expression of E-cadherin. Lasp1 directly interacted with FAK and facilitated the expression of phosphorylated FAK (Tyr397) and AKT (Ser473). Incorporation of both FAK inhibitor and AKT inhibitor counteracted the upregulating expression of Cyclin A2, CyclinB1, and Snail, and downregulating expression of E-cadherin expression induced by Lasp1 overexpression. Interestingly, inhibition of FAK signaling pathway attenuated the phosphorylation of AKT, but inhibition of AKT signaling pathway did not affect the phosphorylation of FAK. In conclusion, Lasp1 facilitated tumor proliferation and invasion of NSCLC through directly binding to FAK and enhancing the phosphorylation of FAK (Tyr397) and AKT (Ser473). Lasp1 may be a novel therapeutic target in the treatment of NSCLC patients.
登录
查看更多内容
影响因子：
--
作者：
Orth MF;Cazes A;Butt E;Grunewald TG
通讯作者：
Grunewald TG
影响因子：
2.9
作者：
Hammarstrom, A;Berndt, KD;Otting, G
通讯作者：
Otting, G
影响因子：
1.9
作者：
Goldstraw, Peter
通讯作者：
Goldstraw, Peter
MicroRNA-29a 通过靶向 LASP1 在非小细胞肺癌细胞中发挥抑制作用。
影响因子：
4
作者：
Hu Z;Cui Y;Zhou Y;Zhou K;Qiao X;Li C;Wang S
通讯作者：
Wang S
影响因子：
3.8
作者：
Fahrmann JF;Grapov D;Phinney BS;Stroble C;DeFelice BC;Rom W;Gandara DR;Zhang Y;Fiehn O;Pass H;Miyamoto S
通讯作者：
Miyamoto S