Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Xuewei, Liu, Li, Wang, Yang, Cong, Jianan, Lin, Zhang, Wang, Yongsen, Liu, Qi, Wang, Leiming, Yang, Ben, Li, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173225/
https://www.ncbi.nlm.nih.gov/pubmed/34094941
http://dx.doi.org/10.3389/fonc.2021.651693
_version_ 1783702683781169152
author Zhu, Xuewei
Liu, Li
Wang, Yang
Cong, Jianan
Lin, Zhang
Wang, Yongsen
Liu, Qi
Wang, Leiming
Yang, Ben
Li, Tao
author_facet Zhu, Xuewei
Liu, Li
Wang, Yang
Cong, Jianan
Lin, Zhang
Wang, Yongsen
Liu, Qi
Wang, Leiming
Yang, Ben
Li, Tao
author_sort Zhu, Xuewei
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8173225
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-81732252021-06-04 lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma Zhu, Xuewei Liu, Li Wang, Yang Cong, Jianan Lin, Zhang Wang, Yongsen Liu, Qi Wang, Leiming Yang, Ben Li, Tao Front Oncol Oncology 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. Frontiers Media S.A. 2021-05-20 /pmc/articles/PMC8173225/ /pubmed/34094941 http://dx.doi.org/10.3389/fonc.2021.651693 Text en Copyright © 2021 Zhu, Liu, Wang, Cong, Lin, Wang, Liu, Wang, Yang and Li https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Zhu, Xuewei
Liu, Li
Wang, Yang
Cong, Jianan
Lin, Zhang
Wang, Yongsen
Liu, Qi
Wang, Leiming
Yang, Ben
Li, Tao
lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
title lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
title_full lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
title_fullStr lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
title_full_unstemmed lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
title_short lncRNA MIAT/HMGB1 Axis Is Involved in Cisplatin Resistance via Regulating IL6-Mediated Activation of the JAK2/STAT3 Pathway in Nasopharyngeal Carcinoma
title_sort lncrna miat/hmgb1 axis is involved in cisplatin resistance via regulating il6-mediated activation of the jak2/stat3 pathway in nasopharyngeal carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173225/
https://www.ncbi.nlm.nih.gov/pubmed/34094941
http://dx.doi.org/10.3389/fonc.2021.651693
work_keys_str_mv AT zhuxuewei lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT liuli lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT wangyang lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT congjianan lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT linzhang lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT wangyongsen lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT liuqi lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT wangleiming lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT yangben lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma
AT litao lncrnamiathmgb1axisisinvolvedincisplatinresistanceviaregulatingil6mediatedactivationofthejak2stat3pathwayinnasopharyngealcarcinoma