Cathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC
Cathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC
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突变体 p53 和 Egr-1 激活的组织蛋白酶 L 促进人 NSCLC 中电离辐射诱导的 EMT
DOI：
10.1186/s13046-019-1054-x
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发表时间：
2019-02-07
影响因子：
11.3
通讯作者：
Liang, Zhongqin
中科院分区：
文献类型：
--
作者：
Wang, Wenjuan;Xiong, Yajie;Liang, Zhongqin
背景辐射（IR）是癌症的主要临床疗法之一，尽管它增加了非小细胞肺癌（NSCLC）的上皮 - 间质转变（EMT）。该作用的潜在细胞和分子机制尚未完全理解。Methodswe使用了NSCLC细胞系以及来自78例NSCLC患者的NSCLC细胞样品，以评估p53，组织蛋白酶L（CTSL）和EMT表型变化。异种移植模型还用于检查突变p53（mut-p53）和CTSL在调节NSCLC的IR诱导的EMT中的作用。与突变体p53（MUT-P53）和p53突变的人NSCLC组织在人NSCLC组织中的反应显着增加与NSCLC患者的转移正相关。在人类非小细胞肺癌细胞系中，用各种p53慢病毒载体转染的H1299细胞可促进IR下（主要通过EMT）在IR下促进细胞的侵袭和运动性。这种EMT过程是通过升高核内CTSL诱导的，核内CTSL受MUT-P53的调节，具体取决于早期生长响应蛋白-1（EGR-1）的激活。在皮下肿瘤异种移植模型中，IR在MUT-P53存在下促进了癌细胞的EMT，由于其下游蛋白CTSL的表达和核转变在一起，这些数据揭示了MUT-P53/ EGR-1/CTSL轴调节负责IR诱导的EMT的信号传导途径。
Ionizing radiation (IR) is one of the major clinical therapies of cancer, although it increases the epithelial-mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC), unexpectedly. The cellular and molecular mechanisms underlying this role are not completely understood. We used NSCLC cell lines as well as tumor specimens from 78 patients with NSCLC to evaluate p53, Cathepsin L (CTSL) and EMT phenotypic changes. Xenograft models was also utilized to examine the roles of mutant p53 (mut-p53) and CTSL in regulating IR-induced EMT of NSCLC. Expression of CTSL was markedly increased in human NSCLC tissues with mutant p53 (mut-p53), and p53 mutation positively correlated with metastasis of NSCLC patients. In human non-small cell lung cancer cell line, H1299 cells transfected with various p53 lentivirus vectors, mut-p53 could promote the invasion and motility of cells under IR, mainly through the EMT. This EMT process was induced by elevating intranuclear CTSL which was regulated by mut-p53 depending on Early growth response protein-1 (Egr-1) activation. In the subcutaneous tumor xenograft model, IR promoted the EMT of the cancer cells in the presence of mut-p53, owing to increase expression and nuclear transition of its downstream protein CTSL. Taken together, these data reveal the role of the mut-p53/Egr-1/CTSL axis in regulating the signaling pathway responsible for IR-induced EMT.