Effects of Interleukin-6 on STAT3-regulated signaling in oral cancer and as a prognosticator of patient survival. (January 2022)

• Record Type: Journal Article
• Authors: Wei, Ling-Ying; Lin, Hsuan-Chao; Tsai, Feng-Chiao; Ko, Jenq-Yuh; Kok, Sang-Heng; Cheng, Shih-Jung; Lee, Jang-Jaer; Chia, Jean-San
• Is Part Of: Oral oncology. Volume 124(2022)
• Publication Date: 2022-01
• Subjects: Oral squamous cell carcinoma -- Patient survival -- IL-6 -- STAT3 -- Anti-apoptosis; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2021.105665
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: IL-6 is a stage-independent prognosticator of patient survival of oral cancer patients. IL-6 enhances tumor growth in both autocrine and paracrine manners. Knockdown or inhibition of STAT3 expression reduces tumor growth and abolished the responsiveness to IL-6 stimulation in OSCC cells. Siltuximab and tocilizumab inhibit IL-6-induced anti-apoptotic gene expression by reducing STAT3 phosphorylation and translocation. 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 proliferation in vitro and significantly enhanced tumor growth in 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.