Effects of Interleukin-6 on STAT3-regulated signaling in oral cancer and as a prognosticator of patient survival

Ling-Ying Wei; Hsuan-Chao Lin; Feng-Chiao Tsai; Jenq-Yuh Ko; Sang-Heng Kok; Shih-Jung Cheng; Jang-Jaer Lee; Jean-San Chia

doi:10.1016/j.oraloncology.2021.105665

Effects of Interleukin-6 on STAT3-regulated signaling in oral cancer and as a prognosticator of patient survival

Oral Oncol. 2022 Jan:124:105665. doi: 10.1016/j.oraloncology.2021.105665. Epub 2021 Dec 8.

Authors

Ling-Ying Wei¹, Hsuan-Chao Lin², Feng-Chiao Tsai³, Jenq-Yuh Ko⁴, Sang-Heng Kok⁵, Shih-Jung Cheng⁵, Jang-Jaer Lee⁵, Jean-San Chia⁶

Affiliations

¹ Department of Dentistry, National Taiwan University Hospital, Bei-hu Branch, Taipei, Taiwan; Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taipei, Taiwan.
² Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
⁶ Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan. Electronic address: chiajs@ntu.edu.tw.

PMID: 34891076
DOI: 10.1016/j.oraloncology.2021.105665

Abstract

Objectives: Human oral squamous cell carcinoma (OSCC) produces an inflammatory microenvironment enriched with cytokines including interleukin-6 (IL-6); however, the underlying molecular mechanisms of OSCC progression are unclear. We aimed to delineate the STAT3-mediated signaling pathways involved in tumor cell survival and growth.

Materials and methods: Immunohistochemistry was used to semi-quantitate IL-6 and STAT3 in 111 OSCC tissues. IL-6-induced STAT3 signaling pathways and effects on tumor cell survival and progression were investigated in vitro and in xenograft mouse models. Effects of blocking IL-6-induced activation of STAT3 in an OSCC cell line were determined in vitro.

Results: A higher level of IL-6 or STAT3 in situ was associated with an unfavorable prognosis in OSCC patients with regard to both disease-free and overall survival rates. Overexpressed or exogenous IL-6 could induce SAS cell proliferationin vitroand significantly enhanced tumor growthin vivo. In addition, knockdown or inhibition of STAT3 expression in SAS cells significantly reduced tumor growth and abolished the responsiveness to IL-6 stimulation. Siltuximab or Tocilizumab could also significantly suppress IL-6-induced STAT3 phosphorylation and STAT3 nuclear translocation, resulting in a significant decrease of downstream anti-apoptotic proteins Bcl-2, Bcl-xL, and survivin.

Conclusion: The IL-6 level in the tumor microenvironment could serve as a stage-independent predictor of OSCC progression and survival. Further, IL-6 may play a role in this disease through STAT3-dependent upregulation of anti-apoptotic genes and subsequent proliferation of tumor cells.

Keywords: Anti-apoptosis; IL-6; Oral squamous cell carcinoma; Patient survival; STAT3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Interleukin-6* / metabolism
Mice
Mouth Neoplasms* / diagnosis
Mouth Neoplasms* / pathology
STAT3 Transcription Factor* / metabolism
Squamous Cell Carcinoma of Head and Neck* / diagnosis
Squamous Cell Carcinoma of Head and Neck* / pathology
Tumor Microenvironment

Substances

IL6 protein, human
Interleukin-6
STAT3 Transcription Factor
STAT3 protein, human