Skip to main content
SpringerLink
Log in

Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

This study addresses the hypothesis that IL-6/STAT3 signaling is of clinical relevance in oropharyngeal squamous cell carcinoma (OPSCC). We evaluated relationships between key components of this pathway in tumors from a unique cohort of n = 59 fully annotated, treatment-naïve patients with OPSCC. The multiplex Opal platform was utilized for immunofluorescence (IF) analysis of tissues to detect IL-6 and phosphorylated STAT3 (pSTAT3), taking into consideration its nuclear versus cytoplasmic localization. Abundant staining for both IL-6 and pSTAT3 was evident in tumor-rich regions of each specimen. IL-6 correlated with cytoplasmic pSTAT3 but not nuclear or total pSTAT3 in this cohort of OPSCC tumors, regardless of p16 status (r = 0.682, p < 0.0001). There was a significant association between increased total pSTAT3, nuclear pSTAT3, cytoplasmic pSTAT3 and IL-6 in p16 negative tumors. Our data indicate STAT3 phosphorylation was a key feature in p16-negative OPSCC tumors. When IL-6 data was stratified by median expression in tumors, there was no association with overall survival. In contrast, both total and nuclear pSTAT3 were significant predictors of poor overall and disease free survival. This strong inverse relationship with overall survival was present in p16 negative tumors for both total and nuclear pSTAT3, but not in p16 positive OPSCC tumors. Together these data indicate that activation of the STAT3 signaling pathway is a marker of p16 negative tumors and relevant to OPSCC prognosis and a potential target for treatment of this more aggressive OPSCC sub-population.

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

Similar content being viewed by others

References

  1. Pignon JP, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14.

    Article  Google Scholar 

  2. Clarke P, et al. Speech and swallow rehabilitation in head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130(S2):S176–80.

    Article  CAS  Google Scholar 

  3. Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.

    Article  CAS  Google Scholar 

  4. Qian G, et al. Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma. Cancer. 2015;121(20):3600–11.

    Article  CAS  Google Scholar 

  5. Wang D, et al. HER3 targeting sensitizes HNSCC to cetuximab by reducing HER3 activity and HER2/HER3 dimerization: evidence from cell line and patient-derived xenograft models. Clin Cancer Res. 2017;23(3):677–86.

    Article  CAS  Google Scholar 

  6. Fayette J, et al. Randomized phase II study of duligotuzumab (MEHD7945A) vs. cetuximab in squamous cell carcinoma of the head and neck (MEHGAN Study). Front Oncol. 2016;6:232.

    Article  Google Scholar 

  7. Saba NF. Commentary: randomized phase II study of duligotuzumab (MEHD7945A) vs. cetuximab in squamous cell carcinoma of the head and neck (MEHGAN Study). Front Oncol. 2017;7:31.

    Article  Google Scholar 

  8. Steuer CE, et al. A correlative analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 expression in oropharyngeal squamous cell carcinoma. Mol Cancer Ther. 2018;17(3):710–6.

    Article  CAS  Google Scholar 

  9. Gao J, Zhao S, Halstensen TS. Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep. 2016;35(6):3265–74.

    Article  CAS  Google Scholar 

  10. Leon X, et al. Expression of IL-1alpha correlates with distant metastasis in patients with head and neck squamous cell carcinoma. Oncotarget 2015;6(35):37398–409.

    Article  Google Scholar 

  11. Guenin S, et al. Interleukin-32 expression is associated with a poorer prognosis in head and neck squamous cell carcinoma. Mol Carcinog. 2014;53(8):667–73.

    CAS  PubMed  Google Scholar 

  12. Green VL, et al. Serum IL10, IL12 and circulating CD4+ CD25 high T regulatory cells in relation to long-term clinical outcome in head and neck squamous cell carcinoma patients. Int J Oncol. 2012;40(3):833–9.

    CAS  PubMed  Google Scholar 

  13. Hathaway B, et al. Multiplexed analysis of serum cytokines as biomarkers in squamous cell carcinoma of the head and neck patients. Laryngoscope. 2005;115(3):522–7.

    Article  CAS  Google Scholar 

  14. Rose-John S, et al. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80(2):227–36.

    Article  CAS  Google Scholar 

  15. Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014;26(1):38–47.

    Article  CAS  Google Scholar 

  16. Scheller J, et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.

    Article  CAS  Google Scholar 

  17. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15(4):234–48.

    Article  CAS  Google Scholar 

  18. Dominguez C, David JM, Palena C. Epithelial-mesenchymal transition and inflammation at the site of the primary tumor. Semin Cancer Biol. 2017;47:177–84.

    Article  CAS  Google Scholar 

  19. Kiesel BF, et al. Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation. Cancer Chemother Pharmacol. 2016;78(6):1225–35.

    Article  CAS  Google Scholar 

  20. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.

    Article  CAS  Google Scholar 

  21. Grandis JR, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci USA. 2000;97(8):4227–32.

    Article  CAS  Google Scholar 

  22. Gaykalova DA, et al. NF-kappaB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma. Int J Cancer. 2015;137(8):1879–89.

    Article  CAS  Google Scholar 

  23. Colomiere M, et al. Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer. 2009;100(1):134–44.

    Article  CAS  Google Scholar 

  24. Squarize CH, et al. Molecular cross-talk between the NFkappaB and STAT3 signaling pathways in head and neck squamous cell carcinoma. Neoplasia 2006;8(9):733–46.

    Article  CAS  Google Scholar 

  25. Verma G, et al. Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers. Cancer Med. 2017;6(3):591–604.

    Article  CAS  Google Scholar 

  26. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.

    Article  CAS  Google Scholar 

  27. Zhang Y, et al. Activation of Stat3 in v-Src-transformed fibroblasts requires cooperation of Jak1 kinase activity. J Biol Chem. 2000;275(32):24935–44.

    Article  CAS  Google Scholar 

  28. Bharti R, Dey G, Mandal M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: a snapshot of IL-6 mediated involvement. Cancer Lett. 2016;375(1):51–61.

    Article  CAS  Google Scholar 

  29. Wendt MK, et al. STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT. 2014;3(1):e28975.

    PubMed  PubMed Central  Google Scholar 

  30. Russo N, et al. Cytokines in saliva increase in head and neck cancer patients after treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(4):483–90 e1.

    Article  Google Scholar 

  31. Zang C, et al. IL-6/STAT3/TWIST inhibition reverses ionizing radiation-induced EMT and radioresistance in esophageal squamous carcinoma. Oncotarget. 2017;8(7):11228–38.

    PubMed  PubMed Central  Google Scholar 

  32. Yadav A, et al. Bazedoxifene enhances the anti-tumor effects of cisplatin and radiation treatment by blocking IL-6 signaling in head and neck cancer. Oncotarget. 2017;8(40):66912–24.

    Article  Google Scholar 

  33. Centurione L, Aiello FB. DNA Repair and Cytokines: TGF-beta, IL-6, and Thrombopoietin as Different Biomarkers of Radioresistance. Front Oncol. 2016;6:175.

    Article  Google Scholar 

  34. Chen Y, et al. IL-6 signaling promotes DNA repair and prevents apoptosis in CD133+ stem-like cells of lung cancer after radiation. Radiat Oncol. 2015;10:227.

    Article  Google Scholar 

  35. Tamatani T, et al. Enhanced radiosensitization and chemosensitization in NF-kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8. Int J Cancer. 2004;108(6):912–21.

    Article  CAS  Google Scholar 

  36. Stanam A, et al. Upregulated interleukin-6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma. Mol Oncol. 2015;9(7):1371–83.

    Article  CAS  Google Scholar 

  37. Matsuoka Y, et al. IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma. Br J Cancer. 2016;115(10):1234–44.

    Article  CAS  Google Scholar 

  38. Mace TA, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018;67(2):320–32.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under Award Numbers P30CA138292 and 1R01CA208253-01 (G. Lesinski).

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA, 30322, USA

    Gregory B. Lesinski, Sreenivas Nannapaneni, Dong M. Shin, Zhuo G. Chen & Nabil F. Saba

  2. Department of Pathology, Winship Cancer Institute of Emory University, Atlanta, USA

    Christopher C. Griffith

  3. Department of Otolaryngology, Emory University School of Medicine, Atlanta, USA

    Mihir Patel

  4. Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, USA

    Wanqi Chen & Zhengjia Chen

  5. Emory Vaccine Center, Emory University, Atlanta, USA

    Rafi Ahmed & Andreas Wieland

Authors
  1. Gregory B. Lesinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sreenivas Nannapaneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher C. Griffith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mihir Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wanqi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhengjia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rafi Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreas Wieland
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dong M. Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhuo G. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nabil F. Saba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dong M. Shin or Nabil F. Saba.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest related to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 14 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lesinski, G.B., Nannapaneni, S., Griffith, C.C. et al. Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma. Head and Neck Pathol 13, 304–312 (2019). https://doi.org/10.1007/s12105-018-0962-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-018-0962-y

Keywords

Search

Navigation