LncRNA-XIST interacts with miR-29c to modulate the chemoresistance of glioma cell to TMZ through DNA mismatch repair pathway.

Peng Du,Renjun Peng,Jian Yuan,Gang Peng,Haiting Zhao,Qing Liu,Yiwei Liao

doi:10.1042/bsr20170696

Abstract

Temozolomide (TMZ) is the most commonly used alkylating agent in glioma chemotherapy. However, growing resistance to TMZ remains a major challenge for clinicians. Recent evidence emphasizes the key regulatory roles of non-coding RNAs (lncRNAs and miRNAs) in tumor biology, including the chemoresistance of cancers. However, little is known about the role and regulation mechanisms of lncRNA cancer X-inactive specific transcripts (XIST) in glioma tumorigenesis and chemotherapy resistance. In the present study, higher XIST expression was observed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. XIST knockdown alone was sufficient to inhibit glioma cell proliferation and to amplify TMZ-induced cell proliferation inhibition. Moreover, XIST knockdown can sensitize TMZ-resistant glioma cells to TMZ. XIST can inhibit miR-29c expression by directly targetting TMZ-resistant glioma cells. DNA repair protein O6-methylguanine-DNA methytransferase (MGMT) plays a key role in TMZ resistance; transcription factor specificity protein 1 (SP1), a regulator of DNA mismatch repair (MMR) key protein MSH6, has been reported to be up-regulated in TMZ-resistant glioma cell lines. In the present study, we show that XIST/miR-29c coregulates SP1 and MGMT expression in TMZ-resistant glioma cell lines. Our data suggest that XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR-29c via SP1 and MGMT. XIST/miR-29c may be a potential therapeutic target for glioma treatment.

Highlights

As the most common brain cancer, glioma accounts for >60% of primary brain tumors in adults [1,2]
In order to investigate the function of X inactive specific transcript (XIST) in glioma, we first evaluated the expression of XIST in 69 paired glioma tissues and peritumoral brain edema (PTBE) tissues using real-time PCR assays
The results showed that XIST expression was up-regulated in glioma tissues, compared with that of the PTBE tissues (Figure 1A)

Summary

Introduction

As the most common brain cancer, glioma accounts for >60% of primary brain tumors in adults [1,2]. In recent years, emerging evidence has regarded non-coding RNAs, including lncRNAs and miRNAs as major regulators of normal development and diseases, including cancer [7-9]. Its role in cancer resistance to chemotherapy has been reported [16,17]; little is known about its expression pattern, biological function and potential mechanism of glioma progression, and the chemoresistance of c 2017 The Author(s).

Methods

Results

Conclusion