AUTHOR=Zhu Xuewei , Liu Li , Wang Yang , Cong Jianan , Lin Zhang , Wang Yongsen , Liu Qi , Wang Leiming , Yang Ben , Li Tao 

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

JOURNAL=Frontiers in Oncology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.651693

DOI=10.3389/fonc.2021.651693

ISSN=2234-943X

ABSTRACT=Cisplatin-based chemotherapy and radiotherapy are the main first-line treatment strategies in 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 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 biological process and differential expression analysis, we find thirteen significantly altered lncRNAs in NPC cell lines. Furthermore, we determine that elevated LncRNA MIAT level upregulates HMGB1 expression, contributing to cisplatin resistance in NPC cells. We find that the deficiency of 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 the cisplatin resistant tumor growth. Most importantly, we provide the clinical evidence showing that the expression level of LncRNA MIAT/HMGB1/IL6 axis was elevated in resistant NPC tumors, which is highly correlated with poor clinical outcome. Our findings identify a novel chemoresistance mechanism regulated by LncRNA MIAT/HMGB1/IL6 axis, which indicates the possibilities that LncRNA MIAT, HMGB1 and IL6 as the biomarkers for chemoresistance and the targets for developing novel strategies to overcome resistance in NPC patients.