Interleukin-6 facilitates tumor progression by inducing ferroptosis resistance in head and neck squamous cell carcinoma

Mingyu Li; Shufang Jin; Zhiyuan Zhang; Hailong Ma; Xi Yang

doi:10.1016/j.canlet.2021.12.011

Interleukin-6 facilitates tumor progression by inducing ferroptosis resistance in head and neck squamous cell carcinoma

Cancer Lett. 2022 Feb 28:527:28-40. doi: 10.1016/j.canlet.2021.12.011. Epub 2021 Dec 10.

Authors

Mingyu Li¹, Shufang Jin², Zhiyuan Zhang³, Hailong Ma⁴, Xi Yang⁵

Affiliations

¹ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China. Electronic address: mingyuli_omf@163.com.
² Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China. Electronic address: shufangjin@126.com.
³ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China. Electronic address: zhiyuan.zhang@sh9hospital.org.cn.
⁴ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China. Electronic address: mahl21@sjtu.edu.cn.
⁵ Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China. Electronic address: yangxi16@163.com.

PMID: 34902522
DOI: 10.1016/j.canlet.2021.12.011

Abstract

Ferroptosis resistance is an important mechanism of tumor progression. Interleukin-6 (IL-6) is a representative inflammatory cytokine during chronic inflammation; however, our current understanding of its regulatory role of ferroptosis during carcinogenesis of head and neck squamous cell carcinoma is limited. Chromatin immunoprecipitation and functional observations were performed to investigate xCT-regulatory function of IL-6. We observed a gradual increase in lipid peroxide 4-hydroxynonenal and IL-6 levels during progression from normal oral mucosa to leukoplakia and HNSCC. Meanwhile, the expression of xCT, a key amino acid antiporter assisting ferroptosis resistance, was correlated with IL-6 levels. The upregulated expression of xCT in HNSCC is associated with poor prognosis. Silencing of xCT inhibited HNSCC cell proliferation in vitro and tumor growth in vivo, inducing ferroptosis. Mechanistically, IL-6 transcriptionally activates xCT expression through the JAK2/STAT3 pathway. Furthermore, IL-6 reversed ferroptosis and growth suppression that was induced by xCT knockdown or ferroptosis inducer erastin. Our results demonstrate the critical role of IL-6-induced ferroptosis resistance during HNSCC carcinogenesis. The IL-6/STAT3/xCT axis acts as a novel mechanism driving tumor progression and thus may potentially be utilized as a target for tumor prevention and therapy.

Keywords: Ferroptosis; Head and neck squamous cell carcinoma; Interleukin-6; Signal transducer and activator of transcription 3; xCT.

Publication types

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

MeSH terms

Animals
Disease Progression
Ferroptosis / genetics*
Humans
Interleukin-6 / metabolism*
Male
Mice
Squamous Cell Carcinoma of Head and Neck / genetics*
Transfection

Substances

Interleukin-6