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配对样同源结构域2B促进人类肺癌的肿瘤进展和抗自噬作用。

Paired-like homeodomain 2B contributes to tumour progression and anti-autophagy in human lung cancer.

作者信息

Wang Chi-Chung, Lin Sheng-Yi, Huang Yu-Han, Hsieh Chia-Hung, Chang Hsiu-Hui, Chen Hsuan-Yu, Weng Chia-Wei, Chang Gee-Chen, Yu Sung-Liang, Chen Jeremy Jw

机构信息

Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University New Taipei, Taiwan.

Institute of Biomedical Sciences, National Chung Hsing University Taichung, Taiwan.

出版信息

Am J Cancer Res. 2021 Oct 15;11(10):4900-4918. eCollection 2021.

Abstract

Paired-like homeodomain transcription factor 2 () is well known to play an essential role in normal embryonic development. Emerging evidence suggests that may be involved in human tumorigenesis, but the role of in tumour progression remains largely unclear. The expression levels of in lung cancer cells were determined by qRT-PCR and Western blot analyses. Gain- and loss-of-function experiments were conducted to investigate the biological roles of in the phenotype of lung cancer cells. Immunofluorescence staining and transmission electron microscopy were used to observe autophagy. The expression level and clinical significance of were determined in a Taiwanese cohort and the Gene Expression Omnibus (GEO) database, respectively. Here, we show that is the most abundant isoform of the bicoid homeodomain family in lung cancer cells. The enforced expression of PITX2B promoted lung cancer tumorigenesis and progression and . The mechanistic analysis revealed that the nuclear localization of PITX2B is correlated with its oncogenic functions and two important nuclear localization signals. In addition, knockdown in lung cancer cells caused a marked increase in autophagy and apoptosis, suggesting that PITX2B plays an important role in lung cancer cell survival. Moreover, a high expression of was associated with a poor overall survival (<0.05) in both Taiwanese non-small-cell lung cancer patients and GEO lung cancer cohorts. These results provide new insight into the contribution of to lung cancer progression, implicate PITX2B as an important component of cell survival signals and further establish as a therapeutic target for lung cancer treatment.

摘要

配对样同源结构域转录因子2(PITX2B)在正常胚胎发育中起着至关重要的作用,这一点广为人知。新出现的证据表明,PITX2B可能参与人类肿瘤发生,但PITX2B在肿瘤进展中的作用仍基本不清楚。通过qRT-PCR和蛋白质免疫印迹分析确定肺癌细胞中PITX2B的表达水平。进行功能获得和功能丧失实验以研究PITX2B在肺癌细胞表型中的生物学作用。采用免疫荧光染色和透射电子显微镜观察自噬。分别在台湾队列和基因表达综合数据库(GEO)中确定PITX2B的表达水平及其临床意义。在此,我们表明PITX2B是肺癌细胞中双尾同源结构域家族中最丰富的亚型。PITX2B的强制表达促进肺癌的肿瘤发生和进展。机制分析表明,PITX2B的核定位与其致癌功能和两个重要的核定位信号相关。此外,肺癌细胞中PITX2B的敲低导致自噬和凋亡显著增加,表明PITX2B在肺癌细胞存活中起重要作用。此外,在台湾非小细胞肺癌患者和GEO肺癌队列中,PITX2B的高表达均与较差的总生存期相关(P<0.05)。这些结果为PITX2B对肺癌进展的作用提供了新的见解,表明PITX2B是细胞存活信号的重要组成部分,并进一步确立PITX2B作为肺癌治疗的靶点。

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