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Zinc finger protein 263 upregulates interleukin 33 and suppresses autophagy to accelerate the malignant progression of non-small cell lung cancer

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Abstract

Purpose

Non-small cell lung cancer (NSCLC) is a complex disease that remains a major public health concern worldwide. One promising avenue for NSCLC treatment is the targeting of transcription factors that regulate key pathways involved in cancer progression. In this study, we investigated the role of the transcription factor ZNF263 in NSCLC and its impact on the regulation of IL33, apoptosis, and autophagy.

Methods

Levels of ZNF263 in tissues and cell lines were identified, after which the effects of its knockdown on cellular malignant behaviors, apoptosis and autophagy were assessed. Based on bioinformatics analysis, ZNF263 was found to bind to IL33 promoter, their mutual relationship was confirmed, as well as the role of IL33 in the regulation of ZNF263. The involvement of ZNF263 in the growth of xenograft tumors was assessed using tumor-bearing nude mouse models.

Results

Experimental results revealed that ZNF263 was upregulated in NSCLC tissue samples and cell lines. Its expression level is positively correlated with cellular malignant behaviors. We further demonstrated that ZNF263 upregulated IL33 expression, which, in turn, promoted the proliferation and migration, inhibited apoptosis and autophagy in NSCLC cells. Furthermore, ZNF263 knockdown reduced the growth of xenograft tumors in nude mice.

Conclusion

This finding suggests that the inhibition of ZNF263 or IL33 may represent a novel therapeutic strategy for NSCLC. Importantly, our results highlight the crucial role of transcription factors in NSCLC and their potential as therapeutic targets.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Suster DI, Mino-Kenudson M. Molecular pathology of primary non-small cell lung cancer. Arch Med Res. 2020;51:784–98.

    Article  CAS  PubMed  Google Scholar 

  2. Tandberg DJ, Tong BC, Ackerson BG, Kelsey CR. Surgery versus stereotactic body radiation therapy for stage I non-small cell lung cancer: a comprehensive review. Cancer. 2018;124:667–78.

    Article  PubMed  Google Scholar 

  3. Donington J, Schumacher L, Yanagawa J. Surgical issues for operable early-stage non-small-cell lung cancer. J Clin Oncol. 2022;40:530–8.

    Article  PubMed  Google Scholar 

  4. Chaft JE, Rimner A, Weder W, Azzoli CG, Kris MG, Cascone T. Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer. Nat Rev Clin Oncol. 2021;18:547–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yu Y, Zeng D, Ou Q, Liu S, Li A, Chen Y, et al. Association of survival and immune-related biomarkers with immunotherapy in patients with non-small cell lung cancer: a meta-analysis and individual patient-level analysis. JAMA Netw Open. 2019;2: e196879.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Arbour KC, Riely GJ. Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review. JAMA. 2019;322:764–74.

    Article  CAS  PubMed  Google Scholar 

  7. Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19:349–64.

    Article  CAS  PubMed  Google Scholar 

  8. Xie C, Zhou X, Liang C, Li X, Ge M, Chen Y, et al. Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer. J Exp Clin Cancer Res. 2021;40:266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25:1037–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu Y, Wu L, Ao H, Zhao M, Leng X, Liu M, et al. Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer. Aging (Albany NY). 2019;11:11440–62.

    Article  CAS  PubMed  Google Scholar 

  11. Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Targeting autophagy in cancer. Cancer. 2018;124:3307–18.

    Article  PubMed  Google Scholar 

  12. Miao X, Xu J, Zhou Y, Zhou Y, Zhuang Z. The expression of p62 in NSCLC and the relationship with chemotherapy. Pract J Cancer. 2017;32:1588–90.

    Google Scholar 

  13. Gao Y, Luo CL, Li LL, Ye GH, Gao C, Wang HC, et al. IL-33 Provides neuroprotection through suppressing apoptotic, autophagic and NF-κB-mediated inflammatory pathways in a rat model of recurrent neonatal seizure. Front Mol Neurosci. 2017;10:423.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gao Y, Ma L, Luo CL, Wang T, Zhang MY, Shen X, et al. IL-33 exerts neuroprotective effect in mice intracerebral hemorrhage model through suppressing inflammation/apoptotic/autophagic pathway. Mol Neurobiol. 2017;54:3879–92.

    Article  CAS  PubMed  Google Scholar 

  15. Zhou X, Feng Y, Liu S, Li C, Teng Y, Li X, et al. IL-33 promotes the growth of non-small cell lung cancer cells through regulating miR-128-3p/CDIP1 signalling pathway. Cancer Manag Res. 2021;13:2379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shani O, Vorobyov T, Monteran L, Lavie D, Cohen N, Raz Y, et al. Fibroblast-derived IL33 facilitates breast cancer metastasis by modifying the immune microenvironment and driving type 2 immunity. Cancer Res. 2020;80:5317–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huang D, Wang X, Liu Y, Huang Z, Hu X, Hu W, et al. Multi-omic analysis suggests tumor suppressor genes evolved specific promoter features to optimize cancer resistance. Brief Bioinform. 2021. https://doi.org/10.1093/bib/bbab040.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cui J, Liu J, Fan L, Zhu Y, Zhou B, Wang Y, et al. A zinc finger family protein, ZNF263, promotes hepatocellular carcinoma resistance to apoptosis via activation of ER stress-dependent autophagy. Transl Oncol. 2020;13: 100851.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yu Z, Feng J, Wang W, Deng Z, Zhang Y, Xiao L, et al. The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically. Oncogene. 2020;39:3163–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: an update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419.

    Article  PubMed  Google Scholar 

  22. Hu H, Miao Y-R, Jia L-H, Yu Q-Y, Zhang Q, Guo A-Y. AnimalTFDB 3.0: a comprehensive resource for annotation and prediction of animal transcription factors. Nucleic Acids Res. 2018;47:D33–8.

    Article  PubMed Central  Google Scholar 

  23. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 2018;9:423–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qu J, Jiang M, Wang L, Zhao D, Qin K, Wang Y, et al. Mechanism and potential predictive biomarkers of immune checkpoint inhibitors in NSCLC. Biomed Pharmacother. 2020;127: 109996.

    Article  CAS  PubMed  Google Scholar 

  26. Passaro A, Brahmer J, Antonia S, Mok T, Peters S. Managing resistance to immune checkpoint inhibitors in lung cancer: treatment and novel strategies. J Clin Oncol. 2022;40:598–610.

    Article  CAS  PubMed  Google Scholar 

  27. Chen J, Shen Y, Wu B, Yang P, Sun G, Liu X, et al. CUR5g, a novel autophagy inhibitor, exhibits potent synergistic anticancer effects with cisplatin against non-small-cell lung cancer. Cell Death Discov. 2022;8:435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu Z, Han X, Ou D, Liu T, Li Z, Jiang G, et al. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl Microbiol Biotechnol. 2020;104:575–87.

    Article  CAS  PubMed  Google Scholar 

  29. Sun L, Yan Y, Lv H, Li J, Wang Z, Wang K, et al. Rapamycin targets STAT3 and impacts c-Myc to suppress tumor growth. Cell Chem Biol. 2022;29:373-385.e376.

    Article  CAS  PubMed  Google Scholar 

  30. Zadeh FA, Raji A, Ali SA, Abdelbasset WK, Alekhina N, Iswanto AH, et al. Autophagy-related chemoradiotherapy sensitivity in non-small cell lung cancer (NSCLC). Pathol Res Pract. 2022;233: 153823.

    Article  CAS  PubMed  Google Scholar 

  31. Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020;19:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang L, Qiang P, Yu J, Miao Y, Chen Z, Qu J, et al. Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer. Autophagy. 2019;15:391–406.

    Article  CAS  PubMed  Google Scholar 

  33. Russell RC, Guan KL. The multifaceted role of autophagy in cancer. Embo j. 2022;41: e110031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu Z, Mar KB, Hanners NW, Perelman SS, Kanchwala M, Xing C, et al. A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB. Nature. 2019;568:249–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Arya R, et al. The lineage-defining transcription factors SOX2 and NKX2-1 determine lung cancer cell fate and shape the tumor immune microenvironment. Immunity. 2018;49:764-779.e769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu P, Wu D, Duan J, Xiao H, Zhou Y, Zhao L, et al. NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway. Redox Biol. 2020;37: 101702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hua Q, Mi B, Xu F, Wen J, Zhao L, Liu J, et al. Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis. Theranostics. 2020;10:4762–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu J, Huang X, Liu D, Ji K, Tao C, Zhang R, et al. Demethyleneberberine induces cell cycle arrest and cellular senescence of NSCLC cells via c-Myc/HIF-1α pathway. Phytomedicine. 2021;91: 153678.

    Article  CAS  PubMed  Google Scholar 

  39. Zhao J, Wang X, Mi Z, Jiang X, Sun L, Zheng B, et al. STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer. Cell Death Dis. 2021;12:493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zheng Q, Dong H, Mo J, Zhang Y, Huang J, Ouyang S, et al. A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance. Theranostics. 2021;11:824–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the Young Talent Development Plan of Changzhou Health Commission [Grant number CZQM2021025], the Science and Technology Project of Changzhou Health Commission [Grant number QN202140], the Clinical Technology Development Foundation of Jiangsu University [Grant numbers JLY2021023, JLY2021031].

Author information

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, WuJin Hospital Affiliated With Jiangsu University, WuJin Clinical College of Xuzhou Medical University, Changzhou, 213017, Jiangsu, People’s Republic of China

    Jiao Xu & Yanjuan Zhou

  2. Department of Cardiothoracic Surgery, WuJin Hospital Affiliated to Jiangsu University, WuJin Clinical College of Xuzhou Medical University, Changzhou, 213017, Jiangsu, People’s Republic of China

    Qiang Wang

  3. Department of Internal Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People’s Republic of China

    Yuxin Liu

  4. Department of Intensive Care Unit, WuJin Hospital Affiliated With Jiangsu University, WuJin Clinical College of Xuzhou Medical University, 2 Yongning North Road, Changzhou, 213017, Jiangsu, People’s Republic of China

    Jianlei Tang

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  1. Jiao Xu
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  2. Yanjuan Zhou
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Contributions

JX and JT contributed to the conception, design and execution. YZ, QW and YL contributed to execution, data collection and analysis. JX contributed to the draft. All the authors approve the final manuscript and confirm the authenticity of the raw data.

Corresponding author

Correspondence to Jianlei Tang.

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Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

The Ethics Committee of WuJin Hospital Affiliated with Jiangsu University approved the current study. All procedures were carried out in conformity with the 1964 Declaration of Helsinki. The subjects were informed of the project and signed an informed consent form.

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Xu, J., Zhou, Y., Wang, Q. et al. Zinc finger protein 263 upregulates interleukin 33 and suppresses autophagy to accelerate the malignant progression of non-small cell lung cancer. Clin Transl Oncol 26, 924–935 (2024). https://doi.org/10.1007/s12094-023-03325-z

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