Queensland University of Technology (QUT), School of Biomedical Sciences, Institute of Health and Biomedical Innovation and Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia.
Br J Cancer. 2020 Aug;123(4):591-603. doi: 10.1038/s41416-020-0899-2. Epub 2020 May 22.
Non-small cell lung cancers (NSCLC) account for 85-90% of all lung cancers. As drug resistance critically impairs chemotherapy effectiveness, there is great need to identify new therapeutic targets. The aims of this study were to investigate the prognostic and therapeutic potential of the copper-metabolism-domain-protein, COMMD4, in NSCLC.
The expression of COMMD4 in NSCLC was investigated using bioinformatic analysis, immunoblotting of immortalised human bronchial epithelial (HBEC) and NSCLC cell lines, qRT-PCR and immunohistochemistry of tissue microarrays. COMMD4 function was additionally investigated in HBEC and NSCLC cells depleted of COMMD4, using small interfering RNA sequences.
Bioinformatic analysis and in vitro analysis of COMMD4 transcripts showed that COMMD4 levels were upregulated in NSCLC and elevated COMMD4 was associated with poor prognosis in adenocarcinoma (ADC). Immunoblotting demonstrated that COMMD4 expression was upregulated in NSCLC cells and siRNA-depletion of COMMD4, decreased cell proliferation and reduced cell viability. Cell death was further enhanced after exposure to DNA damaging agents. COMMD4 depletion caused NSCLC cells to undergo mitotic catastrophe and apoptosis.
Our data indicate that COMMD4 may function as a prognostic factor in ADC NSCLC. Additionally, COMMD4 is a potential therapeutic target for NSCLC, as its depletion induces cancer cell death.
非小细胞肺癌（NSCLC）占所有肺癌的 85-90%。由于耐药性严重影响化疗效果，因此非常需要确定新的治疗靶点。本研究旨在探讨铜代谢结构域蛋白 COMMD4 在 NSCLC 中的预后和治疗潜力。
使用生物信息学分析、永生化人支气管上皮（HBEC）和 NSCLC 细胞系的免疫印迹、qRT-PCR 和组织微阵列的免疫组织化学，研究 COMMD4 在 NSCLC 中的表达。还使用 COMMD4 小干扰 RNA 序列，在 HBEC 和 NSCLC 细胞中耗尽 COMMD4 来研究 COMMD4 的功能。
生物信息学分析和 COMMD4 转录本的体外分析表明，COMMD4 水平在 NSCLC 中上调，并且升高的 COMMD4 与腺癌（ADC）的预后不良相关。免疫印迹表明，COMMD4 在 NSCLC 细胞中的表达上调，并且 siRNA 耗尽 COMMD4 可降低细胞增殖并降低细胞活力。暴露于 DNA 损伤剂后，细胞死亡进一步增强。COMMD4 耗竭导致 NSCLC 细胞发生有丝分裂灾难和细胞凋亡。
我们的数据表明，COMMD4 可能是 ADC NSCLC 的预后因素。此外，COMMD4 是 NSCLC 的潜在治疗靶点，因为其耗尽可诱导癌细胞死亡。
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