Skip to main content

Advertisement

SpringerLink
Log in

Involvement of Intracellular and Extracellular High-Mobility Group Box-1 in the Progression of Esophageal Squamous Cell Carcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

High-mobility group box-1 (HMGB1) is involved in a broad range of inflammatory responses and the progression of various types of malignancy. However, the roles of HMGB1 in the progression of esophageal squamous cell carcinoma (ESCC) are unclear. The aim of this study was to investigate the significance of intracellular and extracellular HMGB1 in ESCC.

Methods

HMGB1 levels were measured in the tissue and plasma of patients with ESCC, or in ESCC cell lines and their conditioned medium. The effects of downregulation of intracellular HMGB1 or upregulation of extracellular HMGB1 on proliferation, cell migration, and invasion were evaluated using proliferation, transwell, and wound healing assays.

Results

Downregulation of HMGB1 expression inhibited cell proliferation, migration, and invasion. On the other hand, upregulation of extracellular HMGB1 level by addition of recombinant HMGB1 promoted the migratory and invasive abilities of ESCC cells through increases of phosphorylation of the signal-regulated kinase 1/2 and NF-κBp65 proteins. These effects of extracellular HMGB1 were attenuated by treatment with recombinant soluble thrombomodulin, which adsorbs HMGB1. The expression of HMGB1 was significantly higher in tumor tissue (p = 0.008), and the concentration of HMGB1 in the plasma was significantly higher in patients with ESCC than in healthy volunteers (p = 0.04). Cancer-specific survival was worse in patients with high concentration of plasma HMGB1 (p = 0.01).

Conclusion

Increase of HMGB1 levels in tumor cells or plasma plays a crucial role in the malignant potential of ESCC. Intracellular and extracellular HMGB1 may be a therapeutic target in ESCC.

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

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015, 136, E359–E386.

    Article  CAS  Google Scholar 

  2. Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014, 371, 2499–2509.

    Article  Google Scholar 

  3. Cohen DJ, Leichman L. Controversies in the treatment of local and locally advanced gastric and esophageal cancers. J Clin Oncol. 2015, 33, 1754–1759.

    Article  Google Scholar 

  4. Goodwin GH, Sanders C, Johns EW. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem. 1973, 38, 14–19.

    Article  CAS  Google Scholar 

  5. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005, 5, 331–342.

    Article  CAS  Google Scholar 

  6. Chuangui C, Peng T, Zhentao Y. The expression of high mobility group box 1 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. Pathol Oncol Res. 2012, 18, 1021–1027.

    Article  Google Scholar 

  7. Ma H, Zheng S, Zhang X, Gong T, Lv X, Fu S, et al. High mobility group box 1 promotes radioresistance in esophageal squamous cell carcinoma cell lines by modulating autophagy. Cell Death Dis. 2019, 10, 136.

    Article  Google Scholar 

  8. Tang D, Kang R, Zeh HJ 3rd, Lotze MT. High-mobility group box 1 and cancer. Biochim Biophys Acta. 2010, 1799, 131–140.

    Article  CAS  Google Scholar 

  9. Wu T, Zhang W, Yang G, Li H, Chen Q, Song R, et al. HMGB1 overexpression as a prognostic factor for survival in cancer: a meta-analysis and systematic review. Oncotarget. 2016, 7, 50417–50427.

    Article  Google Scholar 

  10. Yao X, Zhao G, Yang H, Hong X, Bie L, Liu G. Overexpression of high-mobility group box 1 correlates with tumor progression and poor prognosis in human colorectal carcinoma. J Cancer Res Clin Oncol. 2010, 136, 677–684.

    Article  CAS  Google Scholar 

  11. Chen S, Dong Z, Yang P, Wang X, Jin G, Yu H, et al. Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer Lett. 2017, 394, 22–32.

    Article  CAS  Google Scholar 

  12. Zhang J, Kou YB, Zhu JS, Chen WX, Li S. Knockdown of HMGB1 inhibits growth and invasion of gastric cancer cells through the NF-κB pathway in vitro and in vivo. Int J Oncol. 2014, 44, 1268–1276.

    Article  CAS  Google Scholar 

  13. Chung HW, Lee SG, Kim H, Hong DJ, Chung JB, Stroncek D, et al. Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer. J Transl Med. 2009, 7, 38.

    Article  Google Scholar 

  14. Cheng BQ, Jia CQ, Liu CT, Lu XF, Zhong N, Zhang ZL, et al. Serum high mobility group box chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Dig Liver Dis. 2008, 40, 446–452.

    Article  CAS  Google Scholar 

  15. Shang GH, Jia CQ, Tian H, Xiao W, Li Y, Wang AH, et al. Serum high mobility group box protein 1 as a clinical marker for non-small cell lung cancer. Respir Med. 2009, 103, 1949–1953.

    Article  Google Scholar 

  16. Lee H, Song M, Shin N, Shin CH, Min BS, Kim HS, et al. Diagnostic significance of serum HMGB1 in colorectal carcinomas. PLoS One. 2012, 7, e34318.

    Article  CAS  Google Scholar 

  17. Chung HW, Jang S, Kim H, Lim JB. Combined targeting of high-mobility group box-1 and interleukin-8 to control micrometastasis potential in gastric cancer. Int J Cancer. 2015, 137, 1598–1609.

    Article  CAS  Google Scholar 

  18. Zhu L, Li X, Chen Y, Fang J, Ge Z. High-mobility group Box 1: a novel inducer of the epithelial–mesenchymal transition in colorectal carcinoma. Cancer Lett. 2015, 357, 527–534.

    Article  CAS  Google Scholar 

  19. Candolfi M, Yagiz K, Foulad D, Alzadeh GE, Tesarfreund M, Muhammad AK, et al. Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin Cancer Res. 2009, 15, 4401–4414.

    Article  CAS  Google Scholar 

  20. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, et al. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000, 405, 354–360.

    Article  CAS  Google Scholar 

  21. Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010, 28, 367–388.

    Article  CAS  Google Scholar 

  22. Schlueter C, Weber H, Meyer B, Rogalla P, Röser K, Hauke S, et al. Angiogenetic signaling through hypoxia, HMGB1, an angiogenetic switch molecule. Am J Pathol. 2005, 166, 1259–1263.

    Article  CAS  Google Scholar 

  23. Jube S, Rivera ZS, Bianchi ME, Powers A, Wang E, Pagano I, et al. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. 2012, 72, 3290–3301.

    Article  CAS  Google Scholar 

  24. Esmon CT. Coagulation and inflammation. J Endotoxin Res. 2003, 9, 192–198.

    CAS  PubMed  Google Scholar 

  25. Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest. 2005, 115, 1267–1274.

    Article  CAS  Google Scholar 

  26. Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol. 2008, 28, 1825–1830.

    Article  CAS  Google Scholar 

  27. Shirai Y, Uwagawa T, Shiba H, Shimada Y, Horiuchi T, Saito N, et al. Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-kB activation. Surgery. 2017, 161, 1675–1682.

    Article  Google Scholar 

  28. Hanly AM, Winter DC. The role of thrombomodulin in malignancy. Semin Thromb Hemost. 2007, 33, 673–679.

    Article  CAS  Google Scholar 

  29. Yang Y, Cheng BJ, Lu S. Thrombomodulin regulates doxorubicin sensitivity through epithelial-mesenchymal transition in non-small cell lung cancer. Eur Rev Med Pharmacol Sci. 2017, 21, 95–101.

    CAS  PubMed  Google Scholar 

  30. Sobin LH, Gospodarowicz MK, Wittekind Ch (eds). TNM classification of malignant tumors, 7th edn. Wiley-Blackwell: Hoboken, 2009.

    Google Scholar 

  31. Das N, Dewan V, Grace PM, Gunn RJ, Tamura R, Tzarum N, et al. HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia. Cell Rep. 2016, 17, 1128–1140.

    Article  CAS  Google Scholar 

  32. Zhang L, Chen W, Li X. A novel anticancer effect of butein, inhibition of invasion through the erk1/2 and NF-kappa B signaling pathways in bladder cancer cells. FEBS Lett. 2008, 582, 1821–1828.

    Article  CAS  Google Scholar 

  33. Kumar S, Weaver VM. Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev. 2009, 28, 113–127.

    Article  Google Scholar 

  34. Kao YC, Wu LW, Shi CS, Chu CH, Huang CW, Kuo CP, et al. Downregulation of thrombomodulin, a novel target of Snail, induces tumorigenesis through epithelial-mesenchymal transition. Mol Cell Biol. 2010, 30, 4767–4785.

    Article  CAS  Google Scholar 

  35. Wu CT, Chang YH, Lin P, Chen WC, Chen MF. Thrombomodulin expression regulates tumorigenesis in bladder cancer. BMC Cancer. 2014, 14, 375.

    Article  Google Scholar 

  36. van Beijnum JR, Nowak-Sliwinska P, van den Boezem E, Hautvast P, Buurman WA, Griffioen AW. Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene. 2013, 32, 363–374.

    Article  Google Scholar 

Download references

Acknowledgments

We wish acknowledge Asahi Kasei Pharma (Tokyo, Japan) for providing the human recombinant soluble thrombomodulin. There was no source of funding.

Author information

Authors and Affiliations

  1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Daiki Matsubara MD, Hirotaka Konishi MD, PhD, Tomohiro Arita MD, PhD, Katsutoshi Shoda MD, PhD, Yuji Fujita MD, PhD, Shinpei Ogino MD, PhD, Koji Takao MD, Kenji Nanishi MD, Toshiyuki Kosuga MD, PhD, Shuhei Komatsu MD, PhD, Atsushi Shiozaki MD, PhD, Hitoshi Fujiwara MD, PhD, Kazuma Okamoto MD, PhD & Eigo Otsuji MD, PhD

Authors
  1. Daiki Matsubara MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirotaka Konishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomohiro Arita MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katsutoshi Shoda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuji Fujita MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shinpei Ogino MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koji Takao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenji Nanishi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Toshiyuki Kosuga MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shuhei Komatsu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Atsushi Shiozaki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hitoshi Fujiwara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazuma Okamoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eigo Otsuji MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hirotaka Konishi MD, PhD.

Ethics declarations

Disclosures

The authors declare that there is no conflict of interest.

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 (DOCX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsubara, D., Konishi, H., Arita, T. et al. Involvement of Intracellular and Extracellular High-Mobility Group Box-1 in the Progression of Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 27, 3233–3244 (2020). https://doi.org/10.1245/s10434-020-08363-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-020-08363-3

Search

Navigation