K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway
K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway
复制标题
K-ras 突变部分通过组织蛋白酶 L/CUX1 途径促进电离辐射诱导的肺癌侵袭和迁移
DOI：
10.1016/j.yexcr.2017.12.006
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发表时间：
2018-01-15
影响因子：
3.7
通讯作者：
Liang, Zhongqin
中科院分区：
文献类型：
--
作者：
Wang, Long;Zhao, Yifan;Liang, Zhongqin
K-ras基因突变与肿瘤的侵袭和转移有关，但其机制尚不清楚。组织蛋白酶L是一种溶酶体半胱氨酸蛋白酶，最近发现当其过表达时与人类癌症的侵袭和迁移有关。近年来的研究表明，电离辐射可增强组织蛋白酶L的表达，增强肿瘤细胞的侵袭和迁移能力，但其分子机制尚不清楚。本研究从体内外两方面探讨了K-ras基因突变和IR对肺癌侵袭和迁移的影响及其机制。首先，与111299（K-ras野生型）相比，照射后A549（K-ras突变型）中的组织蛋白酶L和上皮间质转化（EMT）标记蛋白的水平显著改变，从而促进侵袭和迁移。照射后，转染CUX1/p200的A549细胞中组织蛋白酶L及其下游转录因子CUX1/p110的表达增加，而CUX1/p200和组织蛋白酶L-慢病毒共转染H1299细胞后，组织蛋白酶L对CUX1的蛋白水解作用明显增强。此外，将突变K-ras（V12）导入HEK 293细胞后，由于组织蛋白酶L的积累，照射后刺激EMT。此外，突变的K-ras与IR诱导的组织蛋白酶L和EMT在BALB/c裸鼠。最后，携带K-ras突变的样品中组织蛋白酶L表达水平高于野生型K-ras样品，并且间充质标志物在突变K-ras样品中上调，而上皮标志物E-cadherin在非小细胞肺癌组织中下调。研究结果表明，突变的K-ras促进组织蛋白酶L的表达，并在人肺癌的EMT中起关键作用。IR诱导的组织蛋白酶L对肺癌侵袭和迁移的调节作用部分归因于组织蛋白酶L/CUX1介导的EMT信号通路。本研究为组织蛋白酶L作为肿瘤治疗的潜在靶点提供了可能。
K-ras mutation is involved in cancer progression including invasion and migration, but the underlying mechanism is not yet clear. Cathepsin L is a lysosomal cysteine protease and has recently been associated with invasion and migration in human cancers when it is overexpressed. Our recent studies have shown that ionizing radiation (IR) enhanced expression of cathepsin L and increased invasion and migration of tumor cells, but the molecular mechanism is still unclear. In the present study, the effects of K-ras mutation and IR induced invasion and migration of lung cancer as well as the underlying mechanisms were investigated both in vitro and in vivo. Firstly, the levels of cathepsin L and epithelial mesenchymal transition (EMT) marker proteins remarkably changed in A549 (K-ras mutant) after irradiation compared with 111299 (K-ras wild), thereby promoting invasion and migration. Additionally, cathepsin L and its downstream transcription factor CUX1/p110 were increased after irradiation in A549 transfected with CUX1/p200, and the proteolytic processing of CUX1 by cathepsin L was remarkably increased after co-transfection of CUX1/p200 and cathepsin L-lentivirus in H1299. In addition, delivery of a mutant K-ras (V12) into HEK 293 cells stimulated EMT after irradiation due to the accumulation of cathepsin L. Moreover, mutated K-ras was associated with IR-induced cathepsin L and EMT in BALB/c nude mice. Finally, the level of cathepsin L expression was higher in samples carrying a K-ras mutation than in wild-type K-ras samples and the mesenchymal markers were upregulated in the samples of mutant K-ras, whereas the epithelial marker E-cadherin was downregulated in non-small cell lung cancers tissues.In conclusion, the findings demonstrated that mutated K-ras promotes cathepsin L expression and plays a pivotal role in EMT of human lung cancer. The regulatory effect of IR-induced cathepsin L on lung cancer invasion and migration was partially attributed to the Cathepsin L/CUX1-mediated EMT signaling pathway. This study will provide cathepsin L as a potential target for tumor therapy.