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TRIM32 promotes anoikis resistance and metastasis in NSCLC by degrading CHEK2 to enhance IL-6 secretion

Cell Death & Differentiation (2025)Cite this article

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Abstract

Metastasis significantly contributes to the high mortality of non-small cell lung cancer (NSCLC), with anoikis resistance playing a critical role in this process. However, the role of TRIM32 in anoikis resistance and metastasis is not well understood. In this study, we demonstrate that TRIM32 enhances both anoikis resistance and metastasis in NSCLC. We confirmed the interaction between TRIM32 and CHEK2, and showed that TRIM32 mediates the degradation of CHEK2 via K48-linked polyubiquitination. Our results indicate that CHEK2 suppresses anoikis resistance and metastasis in NSCLC, both in vitro and in vivo. Additionally, we found that TRIM32 upregulates IL-6 expression, an effect that is reversed by the overexpression of CHEK2. Further analysis confirmed that IL-6 plays a key role in TRIM32-mediated anoikis resistance and metastasis. Notably, TRIM32+CHEK2-IL-6+ tumor cells were more prevalent in NSCLC tissues with lymph node metastasis. In conclusion, our findings suggest that targeting TRIM32 to inhibit anoikis resistance and metastasis, via the CHEK2/IL-6 axis, may provide a novel therapeutic strategy for treating metastatic NSCLC.

The mechanisms by which TRIM32 promotes anoikis resistance and metastasis in NSCLC. Schematic diagram showing the regulatory mechanisms of TRIM32 promotes anoikis resistance and metastasis in NSCLC by degrading CHEK2 to promote IL-6 secretion.

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Fig. 1: TRIM32 is highly expressed in NSCLC and is highly expressed in anoikis resistant cells.
Fig. 2: Overexpression of TRIM32 promotes anoikis resistance and metastasis in NSCLC.
Fig. 3: Knockout of TRIM32 inhibits anoikis resistance and metastasis in NSCLC.
Fig. 4: TRIM32 degrades CHEK2 through ubiquitination of the K-48 polyubiquitin chain.
Fig. 5: CHEK2 inhibits anoikis resistance and metastasis in NSCLC.
Fig. 6: TRIM32 promotes anoikis resistance and metastasis in NSCLC through CHEK2.
Fig. 7: TRIM32 regulates anoikis resistance and metastasis of NSCLC through IL-6.
Fig. 8: TRIM32+CHEK2-IL-6+ subpopulation of NSCLC cells and metastasis in NSCLC show positive correlation.

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All data generated or analyzed during this study are included in this published article.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535–54.

    Article  PubMed  Google Scholar 

  3. Wang C, Wu Y, Shao J, Liu D, Li W. Clinicopathological variables influencing overall survival, recurrence and post-recurrence survival in resected stage I non-small-cell lung cancer. BMC Cancer. 2020;20:150.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Klein CA. Cancer progression and the invisible phase of metastatic colonization. Nat Rev Cancer. 2020;20:681–94.

    Article  PubMed  CAS  Google Scholar 

  5. Xie S, Wu Z, Qi Y, Wu B, Zhu X. The metastasizing mechanisms of lung cancer: recent advances and therapeutic challenges. Biomed Pharmacother. 2021;138:111450.

    Article  PubMed  CAS  Google Scholar 

  6. Taddei ML, Giannoni E, Fiaschi T, Chiarugi P. Anoikis: an emerging hallmark in health and diseases. J Pathol. 2012;226:380–93.

    Article  PubMed  CAS  Google Scholar 

  7. Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997;9:701–6.

    Article  PubMed  CAS  Google Scholar 

  8. Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis. Cancer Lett. 2008;272:177–85.

    Article  PubMed  CAS  Google Scholar 

  9. Zhan W, Zhang S. TRIM proteins in lung cancer: mechanisms, biomarkers and therapeutic targets. Life Sci. 2021;268:118985.

    Article  PubMed  CAS  Google Scholar 

  10. Bawa S, Piccirillo R, Geisbrecht ER. TRIM32: a multifunctional protein involved in muscle homeostasis, glucose metabolism, and tumorigenesis. Biomolecules. 2021;11:408.

  11. Lazzari E, Meroni G. TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: from muscular dystrophy to tumours. Int J Biochem Cell B. 2016;79:469–77.

    Article  CAS  Google Scholar 

  12. Romagnoli A, Di Rienzo M, Petruccioli E, Fusco C, Palucci I, Micale L, et al. The ubiquitin ligase TRIM32 promotes the autophagic response to Mycobacterium tuberculosis infection in macrophages. Cell Death Dis. 2023;14:505.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chen Z, Tian L, Wang L, Ma X, Lei F, Chen X, et al. TRIM32 inhibition attenuates apoptosis, oxidative stress, and inflammatory injury in podocytes induced by high glucose by modulating the Akt/GSK-3beta/Nrf2 pathway. Inflammation. 2022;45:992–1006.

    Article  PubMed  CAS  Google Scholar 

  14. Di Rienzo M, Antonioli M, Fusco C, Liu Y, Mari M, Orhon I, et al. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Sci Adv. 2019;5:u8857.

    Article  Google Scholar 

  15. Wang C, Xu J, Fu H, Zhang Y, Zhang X, Yang D, et al. TRIM32 promotes cell proliferation and invasion by activating beta-catenin signalling in gastric cancer. J Cell Mol Med. 2018;22:5020–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kano S, Miyajima N, Fukuda S, Hatakeyama S. Tripartite motif protein 32 facilitates cell growth and migration via degradation of Abl-interactor 2. Cancer Res. 2008;68:5572–80.

    Article  PubMed  CAS  Google Scholar 

  17. Huang C. Roles of E3 ubiquitin ligases in cell adhesion and migration. Cell Adhes Migr. 2010;4:10–8.

    Article  Google Scholar 

  18. Chen F, Guo Q, Chen Q, Han Z, Zhou X, Wu L, et al. TRIM32 triggers beta-catenin signaling through ubiquitylation of AXIN1 to promote inflammatory factor-induced apoptosis of rat nucleus pulposus cells. AM J Physiol Cell PH. 2020;318:C695–703.

    Article  Google Scholar 

  19. Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022;19:237–53.

    Article  PubMed  CAS  Google Scholar 

  20. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Perez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Brit J Cancer. 2019;120:6–15.

    Article  PubMed  CAS  Google Scholar 

  21. Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37:11553–72.

    Article  PubMed  CAS  Google Scholar 

  22. Boonen R, Vreeswijk M, van Attikum H. CHEK2 variants: linking functional impact to cancer risk. Trends Cancer. 2022;8:759–70.

    Article  PubMed  CAS  Google Scholar 

  23. Spachmann PJ, Azzolina V, Weber F, Evert M, Eckstein M, Denzinger S, et al. Loss of CHEK2 predicts progression in stage pT1 non-muscle-invasive bladder cancer (NMIBC). Pathol Oncol Res. 2020;26:1625–32.

    Article  PubMed  CAS  Google Scholar 

  24. Suchy J, Cybulski C, Wokolorczyk D, Oszurek O, Gorski B, Debniak T, et al. CHEK2 mutations and HNPCC-related colorectal cancer. Int J Cancer. 2010;126:3005–9.

    Article  PubMed  CAS  Google Scholar 

  25. Stolarova L, Kleiblova P, Janatova M, Soukupova J, Zemankova P, Macurek L, et al. CHEK2 germline variants in cancer predisposition: stalemate rather than checkmate. Cells. 2020;9:2675.

  26. Hu HF, Han L, Fu JY, He X, Tan JF, Chen QP, et al. LINC00982-encoded protein PRDM16-DT regulates CHEK2 splicing to suppress colorectal cancer metastasis and chemoresistance. Theranostics. 2024;14:3317–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Csh Perspect Biol. 2014;6:a16295.

    Google Scholar 

  28. Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL-6) Immunotherapy. Csh Perspect Biol. 2018;10:a028456.

  29. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.

    Article  PubMed  CAS  Google Scholar 

  30. Wang L, Cao L, Wang H, Liu B, Zhang Q, Meng Z, et al. Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway. Oncotarget. 2017;8:76116–28.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Al-Rakan MA, Hendrayani SF, Aboussekhra A. CHEK2 represses breast stromal fibroblasts and their paracrine tumor-promoting effects through suppressing SDF-1 and IL-6. BMC Cancer. 2016;16:575.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We sincerely thank Prof. Dongming Kuang from Sun Yat-sen University for his invaluable guidance and support, which were instrumental in the successful completion of this research. His insightful suggestions and expertise provided critical contributions to the study’s direction and outcomes. We also appreciate the assistance and constructive feedback from our colleagues and collaborators, which significantly enhanced the quality of this work.

Funding

This research was funded by Key Project of Jiangsu Provincial Health Commission (zd2021050), State-level Key Laboratory of Clinical Immunology (Soochow University) (9012280224), Su Zhou Basic Research Pilot Project (SSD2024098), Suzhou Applied Basic research (SKY2022128), National Natural Science Foundation of China (82303146,81872328,81372276,30901789), 2024 Reserve Talent Program (0499980201048, 0302020201048).

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Authors and Affiliations

  1. Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Jia Xu, Wenjun Liu, Li Chen, Juan Zhang, Dongze Zhang, Xue Huang & Guangbo Zhang

  2. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China

    Jia Xu, Wenjun Liu, Li Chen, Juan Zhang, Dongze Zhang, Xue Huang & Guangbo Zhang

  3. School of Life Sciences, Soochow University, Suzhou, China

    Jia Xu & Wenjun Liu

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  1. Jia Xu
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  2. Wenjun Liu
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  3. Li Chen
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  4. Juan Zhang
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  5. Dongze Zhang
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Contributions

Jia Xu, Conceptualisation, Validation, Data Management, Formal Analysis, Writing Originals, Visualisation. Wenjun Liu, Conceptualisation, Formal Analysis, Data Management, Validation. Li Chen, Conceptualisation, Software. Juan Zhang, Software, Investigation. Dongze Zhang, Conceptualisation, Investigation. Xue Huang, Funding Acquisition, Methodology, Project Management, Writing-Review and Editing, Supervision. Guangbo Zhang, Funding Acquisition, Methodology, Project Management, Writing-Review and Editing, Resources.

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Correspondence to Xue Huang or Guangbo Zhang.

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The authors declare no competing interests.

Ethics

All animal experiments were conducted according to the guidelines of the First Affiliated Hospital of Soochow University and approved by the Laboratory Animal Ethics Committee of Soochow University. The present study was approved by the Bioscience Ethics Review Committee of Hunan Aifang Biotechnology Co., Ltd., and all enrolled patients provided written informed consent.

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Xu, J., Liu, W., Chen, L. et al. TRIM32 promotes anoikis resistance and metastasis in NSCLC by degrading CHEK2 to enhance IL-6 secretion. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01559-8

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