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

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.

Chaperonin containing TCP1 subunit 3 (CCT3) promotes cisplatin resistance of lung adenocarcinoma cells through targeting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway

“…Previous work has identified the JAK2/STAT3 pathway to be involved in cisplatin resistance of nasopharyngeal carcinoma [ 16 ] and epirubicin resistance of NSCLCs [ 17 ]. It was also reported that the phosphorylation levels of JAK2 and STAT3 were significantly elevated in cisplatin-resistant NSCLC cell lines compared with those in cisplatin-sensitive NSCLC cell lines [ 39 ].…”

“…The JAK2/STAT3 pathway has been considered a promising target for chemotherapeutic interference ascribed to its persistent activation in human carcinomas [ 14 ]. This pathway is also found to be involved in drug resistance in diverse cancers, such as gemcitabine resistance in pancreatic cancer [ 15 ], cisplatin resistance in nasopharyngeal carcinoma [ 16 ], and epirubicin resistance in NSCLCs [ 17 ].…”

Involvement of Non-Coding RNAs in Chemo- and Radioresistance of Nasopharyngeal Carcinoma

“…Therefore, lncRNA MIAT can be used as a target, and inhibition of lncRNA MIAT expression can reverse chemoresistance in nasopharyngeal carcinoma to some extent. 98 The authors found that lnc NEAT1 interacted with let-7a-5p, and the two were negatively correlated. Let-7a-5p inhibited chemoresistance and improved chemosensitivity in nasopharyngeal carcinoma.…”

“…Zhu et al proved that lncRNAs MIAT and HMGB1 are upregulated in cisplatin-resistant nasopharyngeal carcinoma cells, are biological targets that promote cisplatin resistance, and can initiate the JAK2/STAT3 pathway by promoting the expression level of self-IL6, further increasing cisplatin resistance in nasopharyngeal carcinoma cells. 98 Moreover, Ras-MAPK is an important intracellular signalling pathway that regulates apoptosis, the cell cycle and many other cellular processes. Low expression of NEAT1 inhibited the expression level of let-7a-5p, which reduced the activity of the Ras-MAPK signalling pathway and increased the sensitivity of NPC cells to cisplatin.…”

The Role of lncRNAs in Rare Tumors with a Focus on HOX Transcript Antisense RNA (HOTAIR)

“…More recently, many other lncRNAs have been associated with NPC progression, with their capacity of sponging different microRNAs [ 58 , 61 , 62 , 63 , 71 , 72 , 73 , 74 ]. Additionally, in NPC patients, a large number of lncRNAs were also associated with cisplatin resistance [ 42 , 43 , 44 , 45 , 75 , 76 , 77 , 78 ] and radioresistance [ 54 , 79 , 80 ].…”