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Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy

Authors Jiang P, Wang P, Sun X, Yuan Z, Zhan R, Ma X, Li W

Received 13 September 2015

Accepted for publication 22 December 2015

Published 13 June 2016 Volume 2016:9 Pages 3501—3509

DOI https://doi.org/10.2147/OTT.S96278

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Manfred Beleut

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati


Pengfei Jiang,1,* Ping Wang,2,* Xiaoling Sun,3 Zhongshun Yuan,4 Rucai Zhan,5 Xiangyu Ma,2 Weiguo Li2

1Medical Department, Yuhuangding Hospital, Yantai, 2Neurosurgery Department, Qilu Hospital, Shandong University, Jinan, 3Neurosurgery Department, Yuhuangding Hospital, Yantai, 4Neurosurgery Department, Yinan People’s Hospital, Linyi, 5Neurosurgery Department, No 3 Hospital of Jinan, Jinan, People’s Republic of China

*These authors contributed equally to this work

Abstract: Temozolomide (TMZ) is commonly used in glioma chemotherapy. However, a great clinical challenge for TMZ is chemoresistance. H19 transcripts are recognized as long noncoding RNAs, which potentially interact with chromatin-modifying complexes to regulate gene expression via epigenetic changes. Our data based on glioma patients showed that the expression of H19 was significantly upregulated in TMZ-resistant tumors compared with the TMZ-sensitive tumors. To determine the function of H19 in glioma, cell lines U87 and U251 were exposed to TMZ to establish TMZ-resistant clones U87TMZ and U251TMZ. In U87TMZ and U251TMZ, the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones, as determined by real-time quantitative reverse transcription polymerase chain reaction. Concomitant treatment with small interfering RNA specifically targeting H19 and TMZ in resistant glioma clones resulted in decreased IC50 values for TMZ, and increased apoptotic rates than control small interfering RNA-treated cells. This was also evident by the increased PARP cleavage in resistant cells exposed to TMZ + si-H19. Furthermore, the reduced expression of H19 altered major drug resistance genes, such as MDR, MRP, and ABCG2, both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.

Keywords: glioma, temozolomide, lncRNA, H19, drug resistance

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