2. Academic Validation
  3. 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

  • Environ Pollut. 2022 Dec 27;120943. doi: 10.1016/j.envpol.2022.120943.
Yong Zeng 1,  Hong-Qiang Chen 2,  Zhe Zhang 3,  Jun Fan 3,  Jing-Zhi Li 4,  Shi-Meng Zhou 5,  Na Wang 6,  Su-Peng Yan 7,  Jia Cao 8,  Jin-Yi Liu 8,  Zi-Yuan Zhou 2,  Wen-Bin Liu 9
Affiliations

Affiliations

  • 1 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
  • 2 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
  • 3 Department of Breast and Thyroid Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, PR China.
  • 4 Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; School of Public Health, Xinxiang Medical University, Xinxiang, 453003, PR China.
  • 5 Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, PR China.
  • 6 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, PR China.
  • 7 Department of Biomedical Engineering and Imaging Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
  • 8 Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
  • 9 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China. Electronic address: liuwenbin@tmmu.edu.cn.
PMID: 36584854 DOI: 10.1016/j.envpol.2022.120943
Abstract

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.

Keywords

Apoptosis; Chemical carcinogenesis; DNA methylation; IFI44L; STAT1.

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