IFI44L as a novel epigenetic silencing tumor suppressor promotes apoptosis through JAK/STAT1 pathway during lung carcinogenesis
IFI44L as a novel epigenetic silencing tumor suppressor promotes apoptosis through JAK/STAT1 pathway during lung carcinogenesis
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IFI44L 作为一种新型表观遗传沉默肿瘤抑制因子在肺癌发生过程中通过 JAK/STAT1 通路促进细胞凋亡
DOI：
10.1016/j.envpol.2022.120943
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发表时间：
2023
影响因子：
8.9
通讯作者：
Wen-bin Liu
中科院分区：
文献类型：
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作者：
Yong Zeng;Hong-qiang Chen;Zhe Zhang;Jun Fan;Jing-zhi Li;Shi-meng Zhou;Na Wang;Su-peng Yan;Jia Cao;Jin-yi Liu;Zi-yuan Zhou;Wen-bin Liu
大量证据表明，肺癌的发生、发展与环境污染密切相关。因此，迫切需要新的环境反应预测标志物用于肺癌的早期诊断和筛查。干扰素诱导蛋白44样（IFI 44 L）已被证明与多种肿瘤有关，但其在肺癌发生过程中的功能和机制仍不清楚。本研究通过在线工具和恶性转化模型分析基因表达和甲基化状态。建立了差异表达细胞模型和异种移植瘤模型，并用于阐明基因功能。采用RT-qPCR、Western blotting、免疫组化和免疫共沉淀（Co-IP）等方法探讨其作用机制。结果表明，IFI 44 L在肺癌发生过程中表达显著下调，其低表达可能与DNA甲基化有关。IFI 44 L过表达明显抑制细胞生长，促进细胞凋亡。IFI 44 L表达下调后，细胞增殖能力明显增强，凋亡明显减少。功能富集显示IFI 44 L参与细胞凋亡和JAK/STAT 1信号通路，并与下游分子高度相关。IFI 44 L过表达后，P-STAT 1及其下游分子XAF 1、OAS 1、OAS 2和OAS 3的表达均显著增加。在STAT 1表达敲低后，IFI 44 L的促凋亡作用降低。Co-IP结果显示IFI 44 L与STAT 1存在蛋白质相互作用。结果表明，IFI 44 L通过与STAT 1蛋白直接结合，促进STAT 1磷酸化，激活JAK/STAT 1信号通路，从而导致细胞凋亡。我们的研究表明，IFI 44 L通过激活JAK/STAT 1信号通路促进细胞凋亡并发挥肿瘤抑制作用。IFI 44 L具有临床治疗潜力，可能是肺癌发生过程中一个有前途的生物标志物。
Numerous evidence showed that the occurrence and development of lung cancer is closely related to environmental pollution. Therefore, new environmental response predictive markers are urgently needed for early diagnosis and screening of lung cancer. Interferon-induced protein 44-like (IFI44L) has been shown to be related in a variety of tumors, but its function and mechanism during lung carcinogenesis still have remained largely unknown. In this study, gene expression and methylation status were analyzed through online tools and malignant transformation models. Differentially expressed cell models and xenograft tumor models were established and used to clarify the gene function. RT-qPCR, western blotting, immunohistochemistry, and co-immunoprecipitation (Co-IP) were used to explore the mechanism. Results showed that IFI44L was dramatically downexpressed during lung carcinogenesis, and its low expression may be attributed to DNA methylation. Overexpression of IFI44L obviously inhibited cell growth and promoted apoptosis. After knockdown of IFI44L expression, the proliferation ability was remarkably increased and the apoptosis was significantly reduced. Functional enrichment showed that IFI44L was involved in apoptosis and JAK/STAT1 signaling pathway, and was highly correlated with downstream molecules. After overexpression of IFI44L, the expression of P-STAT1 and downstream molecules XAF1, OAS1, OAS2 and OAS3 were significantly increased. After knockdown of STAT1 expression, the pro-apoptotic effect of IFI44L was reduced. Co-IP results showed that IFI44L had protein interaction with STAT1. Results proved that IFI44L promoted STAT1 phosphorylation and activated the JAK/STAT1 signaling pathway by directly binding to STAT1 protein, thereby leading to cell apoptosis. Our study revealed that IFI44L promotes cell apoptosis and exerts tumor suppressors by activating the JAK/STAT1 signaling pathway. It further suggests that IFI44L has clinical therapeutic potential and may be a promising biomarker during lung carcinogenesis.