Home High-mobility group box 3 (HMGB3) silencing inhibits non-small cell lung cancer development through regulating Wnt/β-catenin pathway
Article
Licensed
Unlicensed Requires Authentication

High-mobility group box 3 (HMGB3) silencing inhibits non-small cell lung cancer development through regulating Wnt/β-catenin pathway

  • Yunjing Li , Yongfu Ma , Tong Zhang , Changjiang Feng EMAIL logo and Yang Liu EMAIL logo
Published/Copyright: July 16, 2020

Abstract

It has been reported that high-mobility group box 3 is overexpressed in various cancers. This study aimed to explore its function in non-small cell lung cancer (NSCLC). A546 and H460 cell lines were used for in vivo experiments, scratch healing tests, transwell migration and invasion experiments. It was first found that HMGB3 was highly expressed in tumor tissues in the patients and associated with NSCLC stage. Silencing of HMGB3 significantly slowed the growth, proliferation and invasion of NSCLC in vitro, and repressed cell growth in vivo. Mechanistic studies suggest that the observed effects were mediated by inhibiting the expression of β-catenin/MMP7/c-Myc in Wnt pathway. Our study highlights the role of HMGB3 in NSCLC, which may provide a therapeutic target for the treatment of NSCLC.


Corresponding authors: Changjiang Feng and Yang Liu, Department of Thoracic Surgery, PLA General Hospital, Beijing100853, China, E-mail: (C. Feng), (Y. Liu)

  1. Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research Funding: This work was supported by the National Natural Science Foundation of China (21876205, 81573026).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Conflict of interest statement: The authors declare that they have no competing interests.

References

Alderton, G.K. (2012). Signalling: new roles for TLR2. Nat. Rev. Immunol. 12: 810–811, https://doi.org/10.1038/nrc3407.Search in Google Scholar PubMed

Andersson, U. and Tracey, K.J. (2011). HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29: 139–162, https://doi.org/10.1146/annurev-immunol-030409-101323.Search in Google Scholar PubMed PubMed Central

Avgousti, D.C., Herrmann, C., Kulej, K., Pancholi, N.J., Sekulic, N., Petrescu, J., Molden, R.C., Blumenthal, D., Paris, A.J., Reyes, E.D. et al. (2016). A core viral protein binds host nucleosomes to sequester immune danger signals. Nature 535: 173–177, https://doi.org/10.1038/nature18317.Search in Google Scholar PubMed PubMed Central

Cleary, A.S., Leonard, T.L., Gestl, S.A., and Gunther, E.J. (2014). Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 508: 113–117, https://doi.org/10.1038/nature13187.Search in Google Scholar PubMed PubMed Central

Eubelen, M., Bostaille, N., Cabochette, P., Gauquier, A., Tebabi, P., Dumitru, A.C., Koehler, M., Gut, P., Alsteens, D., Stainier, D.Y.R. et al. (2018). A molecular mechanism for Wnt ligand-specific signaling. Sci. 361, https://doi.org/10.1126/science.aat1178.Search in Google Scholar PubMed

Gong, Y., Cao, Y., Song, L., Zhou, J., Wang, C., and Wu, B. (2013). HMGB3 characterization in gastric cancer. Genet. Mol. Res. 12: 6032–6039.10.4238/2013.December.2.1Search in Google Scholar PubMed

Gu, J., Xu, T., Huang, Q.H., Zhang, C.M., and Chen, H.Y. (2019). HMGB3 silence inhibits breast cancer cell proliferation and tumor growth by interacting with hypoxia-inducible factor 1α. Cancer Manag. Res. 11: 5075–5089, https://doi.org/10.2147/CMAR.S204357.10.2147/CMAR.S204357Search in Google Scholar PubMed PubMed Central

Herbst, R.S., Morgensztern, D., and Boshoff, C. (2018). The biology and management of non-small cell lung cancer. Nature 553: 446–454, https://doi.org/10.1038/nature25183.Search in Google Scholar PubMed

Hiley, C.T., Le Quesne, J., Santis, G., Sharpe, R., de Castro, D.G., Middleton, G., and Swanton, C. (2016). Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Lancet 388: 1002–1011.10.1016/S0140-6736(16)31340-XSearch in Google Scholar PubMed

Ho, J.C. and Leung, C.C. (2018). Management of co-existent tuberculosis and lung cancer. Lung Cancer 122: 83–87.10.1016/j.lungcan.2018.05.030Search in Google Scholar PubMed

Jamal-Hanjani, M., Wilson, G.A., McGranahan, N., Birkbak, N.J., Watkins, T.B.K., Veeriah, S., Shafi, S., Johnson, D.H., Mitter, R., Rosenthal, R. et al. (2017). Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376: 2109–2121, https://doi.org/10.1056/NEJMoa1616288.Search in Google Scholar PubMed

Lee, S., Nam, Y., Koo, J.Y., Lim, D., Park, J., Ock, J., Kim, J., Suk, K., and Park, S.B. (2014). A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat. Chem. Biol. 10: 1055–1060, https://doi.org/10.1038/nchembio.1669.Search in Google Scholar PubMed

Nemeth, M.J., Kirby, M.R., and Bodine, D.M. (2006). Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation. Proc. Natl. Acad. Sci. USA 103: 13783–13788, https://doi.org/10.1073/pnas.0604006103.Search in Google Scholar PubMed PubMed Central

Niehrs, C. (2012). The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13: 767–779.10.1038/nrm3470Search in Google Scholar PubMed

Nusse, R. and Clevers, H. (2017). Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169: 985–999, https://doi.org/10.3322/caac.21390.Search in Google Scholar PubMed

Rami-Porta, R., Asamura, H., Travis, W.D., and Rusch, V.W. (2017). Lung cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J. Clin. 67: 138–155, https://doi.org/10.3322/caac.21390.Search in Google Scholar

Reck, M. and Rabe, K.F. (2017). Precision diagnosis and treatment for advanced non-small-cell lung cancer. N. Engl. J. Med. 377: 849–861, https://doi.org/10.1056/NEJMra1703413.Search in Google Scholar PubMed

Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J., Lee, W., Yuan, J., Wong, P., Ho, T.S. et al. (2015). Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348: 124–128, https://doi.org/10.1126/science.aaa1348.Search in Google Scholar PubMed PubMed Central

Rotow, J. and Bivona, T.G. (2017). Understanding and targeting resistance mechanisms in NSCLC. Nat. Rev. Cancer 17: 637–658.10.1038/nrc.2017.84Search in Google Scholar PubMed

Skinner, M. (2010). Autophagy: in the hands of HMGB1. Nat. Rev. Mol. Cell Biol. 11: 756–757, https://doi.org/10.1038/nrm2994.Search in Google Scholar PubMed

Somervaille, T.C., Matheny, C.J., Spencer, G.J., Iwasaki, M., Rinn, J.L., Witten, D.M., Chang, H.Y., Shurtleff, S.A., Downing, J.R., and Cleary, M.L. (2009). Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell 4: 129–140.10.1016/j.stem.2008.11.015Search in Google Scholar PubMed PubMed Central

Song, N., Liu, B., Wu, J.L., Zhang, R.F., Duan, L., He, W.S., and Zhang, C.M. (2013). Prognostic value of HMGB3 expression in patients with non-small cell lung cancer. Tumour Biol. 34: 2599–2603, https://doi.org/10.1007/s13277-013-0807-y.Search in Google Scholar PubMed

Tammela, T., Sanchez-Rivera, F.J., Cetinbas, N.M., Wu, K., Joshi, N.S., Helenius, K., Park, Y., Azimi, R., Kerper, N.R., Wesselhoeft, R.A. et al. (2017). A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature 545: 355–359, https://doi.org/10.1038/nature22334.Search in Google Scholar PubMed PubMed Central

Wang, J., Sheng, Z., and Cai, Y. (2019a). Effects of microRNA-513b on cell proliferation, apoptosis, invasion, and migration by targeting HMGB3 through regulation of mTOR signaling pathway in non-small-cell lung cancer. J. Cell Physiol. 234: 10934–10941, https://doi.org/10.1002/jcp.27921.Search in Google Scholar PubMed

Wang, K., Yin, Y.H., Yang, Z.Q., Yu, H.F., Wang, Y.S., Guo, B., and Yue, Z.P. (2019b). Hmgb3 induces the differentiation of uterine stromal cells through targeting Ptn. Reprod. Sci. 26: 891–899, https://doi.org/10.1177/1933719118792098.Search in Google Scholar PubMed

Wolffe, A.P. (1999). Architectural regulations and Hmg1. Nat. Genet. 22: 215–217, https://doi.org/10.1038/10267.Search in Google Scholar PubMed

Yan, K.S., Janda, C.Y., Chang, J., Zheng, G.X.Y., Larkin, K.A., Luca, V.C., Chia, L.A., Mah, A.T., Han, A., Terry, J.M. et al. (2017). Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal. Nature 545: 238–242, https://doi.org/10.1038/nature22313.Search in Google Scholar PubMed PubMed Central

Yanai, H., Ban, T., Wang, Z., Choi, M.K., Kawamura, T., Negishi, H., Nakasato, M., Lu, Y., Hangai, S., Koshiba, R. et al. (2009). HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462: 99–103, https://doi.org/10.1038/nature08512.Search in Google Scholar PubMed


Supplementary material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0144).


Received: 2020-02-27
Accepted: 2020-05-05
Published Online: 2020-07-16
Published in Print: 2020-09-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 30.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2020-0144/html
Scroll to top button