Skip to main content

Advertisement

SpringerLink
Log in

E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression

  • Research
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy.

Methods

We first confirmed SOCS3 expression level in patients’ tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells.

Results

We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway.

Conclusion

Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, Cancer Statistics, 2021. CA Cancer J Clin. 71(1), 7–33 (2021)

  2. K.D. Miller, L. Nogueira, A.B. Mariotto, J.H. Rowland, K.R. Yabroff, C.M. Alfano et al., Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 69(5), 363–385 (2019)

    Article  PubMed  Google Scholar 

  3. W.-L. Tan, A. Jain, A. Takano, E.W. Newell, N.G. Iyer, W.-T. Lim et al., Novel therapeutic targets on the horizon for Lung cancer. Lancet Oncol. 17(8), e347–e62 (2016)

    Article  CAS  PubMed  Google Scholar 

  4. X. Hu, J. Li, M. Fu, X. Zhao, W. Wang, The JAK/STAT signaling pathway: from bench to clinic. Signal. Transduct. Target. Ther. 6(1), 402 (2021)

    Article  PubMed  PubMed Central  Google Scholar 

  5. K. Inagaki-Ohara, T. Kondo, M. Ito, A. Yoshimura, SOCS, inflammation, and cancer. JAKSTAT. 2(3), e24053 (2013)

    PubMed  PubMed Central  Google Scholar 

  6. J.J. Babon, N.A. Nicola, The biology and mechanism of action of suppressor of cytokine signaling 3. Growth Factors. 30(4), 207–219 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. L. Dai, Z. Li, Y. Tao, W. Liang, W. Hu, S. Zhou et al., Emerging roles of suppressor of cytokine signaling 3 in human cancers. Biomed. Pharmacother. 144, 112262 (2021)

    Article  CAS  PubMed  Google Scholar 

  8. Y. Ben-Neriah, M. Karin, Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat. Immunol. 12(8), 715–723 (2011)

    Article  CAS  PubMed  Google Scholar 

  9. R. Caruso, N. Warner, N. Inohara, G. Nunez, NOD1 and NOD2: signaling, host defense, and inflammatory Disease. Immunity. 41(6), 898–908 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. M.L. Disis, Immune regulation of cancer. J. Clin. Oncol. 28(29), 4531–4538 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. M.J. Smyth, G.P. Dunn, R.D. Schreiber, Cancer Immunosurveillance and Immunoediting: The Roles of Immunity in Suppressing Tumor Development and Shaping Tumor Immunogenicity. Adv. Immunol. 90, 1–50 (2006)

  12. M.A. Huber, N. Azoitei, B. Baumann, S. Grünert, A. Sommer, H. Pehamberger et al., NF-κB is essential for epithelial-mesenchymal transition and Metastasis in a model of Breast cancer progression. J. Clin. Invest. 114(4), 569–581 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. H.J. Maier, U. Schmidt-Strassburger, M.A. Huber, E.M. Wiedemann, H. Beug, T. Wirth, NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 295(2), 214–228 (2010)

    Article  CAS  PubMed  Google Scholar 

  14. S.J. Kim, T. Hyeong Lee, S. Hee Nam, J.H. Kim, S. Oh, Y. Sook Cho et al., Association of Uba6-Specific-E2 (USE1) with Lung Tumorigenesis. J. Natl. Cancer Inst. 109(3), 1–11 (2017)

    Article  PubMed  Google Scholar 

  15. J.O. Jin, G.D. Lee, S.H. Nam, T.H. Lee, D.H. Kang, J.K. Yun et al., Sequential ubiquitination of p53 by TRIM28, RLIM, and MDM2 in lung tumorigenesis. Cell. Death Differ. 28(6), 1790–1803 (2021)

    Article  CAS  PubMed  Google Scholar 

  16. K.H. Lee, A. Biswas, Y.J. Liu, K.S. Kobayashi, Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components. J. Biol. Chem. 287(47), 39800–39811 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. X. Ma, Y. Qiu, Y. Sun, L. Zhu, Y. Zhao, T. Li et al., NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway. Cell. Death Dis. 11(3), 174 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. S.M.N. Udden, L. Peng, J.L. Gan, J.M. Shelton, J.S. Malter, L.V. Hooper et al., NOD2 suppresses colorectal tumorigenesis via downregulation of the TLR pathways. Cell. Rep. 19(13), 2756–2770 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. T. Kawai, S. Akira, The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol. 21(4), 317–337 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. F.R. Hirsch, G.V. Scagliotti, J.L. Mulshine, R. Kwon, W.J. Curran, Y.-L. Wu et al., Lung cancer: current therapies and new targeted treatments. The Lancet. 389(10066), 299–311 (2017)

    Article  CAS  Google Scholar 

  21. Y. Yin, W. Liu, Y. Dai, SOCS3 and its role in associated Diseases. Hum. Immunol. 76(10), 775–780 (2015)

    Article  CAS  PubMed  Google Scholar 

  22. L.H. Jiang, Y.L. Hao, J.W. Zhu, Expression and prognostic value of HER-2/neu, STAT3 and SOCS3 in hepatocellular carcinoma. Clin. Res. Hepatol. Gastroenterol. 43(3), 282–291 (2019)

    Article  CAS  PubMed  Google Scholar 

  23. K. Inagaki-Ohara, H. Mayuzumi, S. Kato, Y. Minokoshi, T. Otsubo, Y.I. Kawamura et al., Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice. Oncogene. 33(1), 74–84 (2014)

    Article  CAS  PubMed  Google Scholar 

  24. M. Ying, D. Li, L. Yang, M. Wang, N. Wang, Y. Chen et al., Loss of SOCS3 expression is associated with an increased risk of recurrent Disease in breast carcinoma. J. Cancer Res. Clin. Oncol. 136(10), 1617–1626 (2010)

    Article  CAS  PubMed  Google Scholar 

  25. Y. Dong, S. Wang, C. Wang, Z. Li, Y. Ma, G. Liu, Antagonizing NOD2 Signaling with conjugates of Paclitaxel and Muramyl dipeptide derivatives sensitizes Paclitaxel Therapy and significantly prevents Tumor Metastasis. J. Med. Chem. 60(3), 1219–1224 (2017)

    Article  CAS  PubMed  Google Scholar 

  26. D.P. Chen, W.R. Ning, X.F. Li, Y. Wei, X.M. Lao, J.C. Wang et al., Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma. Autophagy. 14(8), 1335–1346 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. T. Yamaoka, S. Arata, M. Homma, T. Homma, S. Kusumoto, K. Ando et al., Blockade of EGFR activation promotes TNF-Induced Lung epithelial cell apoptosis and Pulmonary Injury. Int. J. Mol. Sci. 20(16), 4021 (2019)

Download references

Acknowledgements

All authors have also read the journal’s author agreement and manuscript has been reviewed and approved by all authors.

Funding

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MIST) (NRF-2022R1A2C4002045, RS-2023-00208173, RS-2023-00207868).

Author information

Author notes

  1. In-ho Jeong, Jae Kwang Yun, and Jun-O Jin contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea

    In-ho Jeong & Peter Chang-Whan Lee

  2. Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea

    Jae Kwang Yun & Geun Dong Lee

  3. Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea

    Jun-O Jin

  4. Department of Physiology, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea

    Jeong Hee Hong

  5. Division of Rheumatology, Department of Medicine, Seoul St. Mary’s Hospital, Catholic University, Seoul, 06591, Korea

    Ji Yeon Lee

  6. Lung Cancer Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea

    Geun Dong Lee & Peter Chang-Whan Lee

Authors
  1. In-ho Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae Kwang Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun-O Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeong Hee Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ji Yeon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Geun Dong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Chang-Whan Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PL and GL conceptualization, IJ, JJ, JH JL, and PCL Formal analysis and investigation, Writing - original draft preparation, JY, JL, GL, PL Clinical specimen collection, Data analysis, Statistical analysis, IJ and PL Writing manuscript.All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ji Yeon Lee, Geun Dong Lee or Peter Chang-Whan Lee.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Patient’s lung tissue samples Written informed consent was obtained from all the lung cancer patients who participated in this study. All experimental protocols were approved by the Institutional Review Board of Asan Medical Center and the University of Ulsan College of Medicine (2014 − 0960, 2020 − 1117). Human lung tissues were obtained through the Asan Bio Resource Center (2014-20(89)).

Animal studies All mice were bred at the animal facilities of the Asan Institute for Life Sciences, University of Ulsan College of Medicine. All animal procedures were approved by the Institutional Ethics Committee and Institutional Animal Care Committee of University of Ulsan College of Medicine (2016-02-168 and 2017-12-281).

Consent for publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeong, Ih., Yun, J.K., Jin, JO. et al. E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression. Cell Oncol. (2023). https://doi.org/10.1007/s13402-023-00896-5

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13402-023-00896-5

Keywords

Search

Navigation