lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma

Xuewei Zhu; Li Liu; Yang Wang; Jianan Cong; Zhang Lin; Yongsen Wang; Qi Liu; Leiming Wang; Ben Yang; Tao Li

doi:10.3389/fonc.2021.651693

lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma

Front Oncol. 2021 May 20:11:651693. doi: 10.3389/fonc.2021.651693. eCollection 2021.

Authors

Xuewei Zhu¹, Li Liu², Yang Wang³, Jianan Cong⁴, Zhang Lin⁵, Yongsen Wang⁶, Qi Liu⁷, Leiming Wang⁸, Ben Yang⁵, Tao Li⁹

Affiliations

¹ Department of Otolaryngology Head & Neck Surgery, China Japan Union Hospital of Jilin University, Changchun, China.
² Reproductive Medical Center, Department of Gynecology and Obstetrics, China-Japan Union Hospital of Jilin University, Changchun, China.
³ Department of Dermatology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China.
⁴ Department of Ophthalmology, Changchun City Central Hospital, Changchun, China.
⁵ Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun, China.
⁶ Technology Department, Harbin Boshixuan Technology Co., Ltd, Harbin, China.
⁷ Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
⁸ Shenzhen Bay Laboratory, The Institute of Chemical Biology, Gaoke International Innovation Center, Shenzhen, China.
⁹ Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China.

Abstract

Cisplatin-based chemotherapy and radiotherapy are the main first-line treatment strategies for nasopharyngeal carcinoma (NPC) patients. Unfortunately, resistance is a major obstacle in the clinical management of NPC patients. We prove that the expression level of high-mobility group box 1 (HMGB1) is dramatically increased in resistant NPC cells than that in sensitive cells. HMGB1 induces the expression and secretion of IL6, which leads to constitutive autocrine activation of the JAK2/STAT3 pathway and eventually contributes to chemoresistance in NPC cells. Long non-coding RNAs (lncRNAs) have been identified as key regulators involved in drug resistance. In this study, using GO analysis of the biological process and differential expression analysis, we find 12 significantly altered IncRNAs in NPC cell lines, which may be involved in regulating gene expression. Furthermore, we determine that elevated lncRNA MIAT level upregulates HMGB1 expression, contributing to cisplatin resistance in NPC cells. We find that the deficiency of the lncRNA MIAT/HMGB1 axis, inhibition of JAK2/STAT3, or neutralization of IL6 by antibodies significantly re-sensitizes resistant NPC cells to cisplatin in resistant NPC cells. Moreover, we provide the in vivo evidence that the deficiency of HMGB1 reduces cisplatin-resistant tumor growth. Most importantly, we provide clinical evidence showing that the expression level of the lncRNA MIAT/HMGB1/IL6 axis is elevated in resistant NPC tumors, which is highly correlated with poor clinical outcome. Our findings identify a novel chemoresistance mechanism regulated by the lncRNA MIAT/HMGB1/IL6 axis, which indicates the possibilities for lncRNA MIAT, HMGB1, and IL6 as biomarkers for chemoresistance and targets for developing novel strategies to overcome resistance in NPC patients.

Keywords: HMGB1; IL6; NPC; cisplatin resistance; lncRNA MIAT.