title: MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression.
abstract: Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited therapeutic options. Temozolomide (TMZ) is a novel cytotoxic agent used as first-line chemotherapy for GBM, however, some individual cells can't be isolated for surgical resection and show treatment-resistance, thus inducing poor prognosis. By using the HiSeq sequencing and bioinformatics methods, we identified lncRNAs showing different expression levels in TMZ-resistant and non-resistant patients. RT-qPCR was then performed in tissues and serum samples, and lncRNA MALAT1 was finally identified to show considerable discriminating potential to identify responding patients from non-responding patients. Moreover, high serum MALAT1 expression was associated with poor chemoresponse and survival in GBM patients receiving TMZ treatment. Subsequently, the TMZ resistant cell lines were established, and the CCK8 assay showed that lncRNA MALAT1 knockdown significantly reversed TMZ resistance in GBM cells. The gain and loss-function experiments revealed that miR-203 was down-regulated by MALAT1 and this interaction has reciprocal effects. Besides, thymidylate synthase (TS) mRNA was identified as a direct target of miR-203. LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR-203 and down-regulating TS expression. On the other hand, MALAT1 overexpression promoted resistance by suppressing miR-203 and promoting TS expression. In conclusion, our integrated approach demonstrates that enhanced expression of lncRNA MALAT1 confers a potent poor therapeutic efficacy and inhibition of MALAT1 levels could be a future direction to develop a novel therapeutic strategy to overcome TMZ resistance in GBM patients.
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.|Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.|State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
authors.forename: Xin-Ke
authors.initials: XK
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.|Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Jun-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.|Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Kuan-Kei
authors.initials: KK
authors.lastname: Kong
authors.affiliation: Department of Respiratory, The First People's Hospital of Foshan, Sun Yat-Sen University, Guangdong Foshan 528000, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Oncology, The Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu, China.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Ge
authors.affiliation: Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.|Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Fang-Cheng
authors.initials: FC
authors.lastname: Li
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D015996:Survival Rate; D000077204:Temozolomide; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C557041:MALAT1 long non-coding RNA, human; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D003606:Dacarbazine; D013940:Thymidylate Synthase; D000077204:Temozolomide
keywords: MALAT1; chemoresistance; miR-203; temozolomide; thymidylate synthase