Hung Pei-Shan, Huang Ming-Hung, Kuo Yuan-Yeh, Yang James Chih-Hsin
Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Tai-Chen Cell Therapy Center, National Taiwan University, Taipei 100, Taiwan.
Cancers (Basel). 2020 Mar 31;12(4):837. doi: 10.3390/cancers12040837.
The mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRAS/KRAS mutations and inhibited the KRAS mediated metastasis by Wnt inhibitor. First, we found that KRAS induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRAS cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRAS induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRAS cells. The restored activation of Wnt/β-catenin in H838KRAS cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRAS-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by mutations. Our data indicate that KRAS driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRAS/KRAS is distinct.
这些突变一直是癌症治疗中识别治疗靶点的障碍。在这项研究中，我们阐明了由KRAS/KRAS突变诱导的非小细胞肺癌（NSCLC）的独特转移模式，并通过Wnt抑制剂抑制了KRAS介导的转移。首先，我们发现在体外和体内实验中KRAS诱导了更具侵袭性的表型。H838 KRAS细胞的基因集富集分析（GSEA）结果显示与RhoA相关信号呈显著负相关。顺着这条线索，我们观察到在H838KRAS细胞中KRAS诱导了更高的RhoA激活并抑制了Wnt/β-连环蛋白的激活。当用RhoA的显性负性突变体表达或用RhoA抑制剂处理时，可以检测到H838KRAS细胞中Wnt/β-连环蛋白的激活恢复。此外，Wnt抑制剂消除了KRAS诱导的迁移。我们阐明了RhoA/Wnt轴在由突变驱动的NSCLC转移调控中的重要性。我们的数据表明，KRAS驱动的NSCLC转移是Wnt依赖性的，并且由KRAS/KRAS诱导的NSCLC转移机制是不同的。
