title: miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression.
abstract: Genome-wide microRNA (miRNA) profiling of 82 glioblastomas demonstrated that miR-181d was inversely associated with patient overall survival after correcting for age, Karnofsky performance status, extent of resection, and temozolomide (TMZ) treatment. This association was validated using the Cancer Genome Atlas (TCGA) dataset (n= 424) and an independent cohort (n= 35). In these independent cohorts, an association of miR-181d with survival was evident in patients who underwent TMZ treatment but was not observed in patients without TMZ therapy. Bioinformatic analysis of potential genes regulated by miR-181d revealed methyl-guanine-methyl-transferase (MGMT) as a downstream target. Indeed, transfection of miR-181d downregulated MGMT mRNA and protein expression. Furthermore, luciferase reporter assays and coprecipitation studies showed a direct interaction between miR-181d and MGMT 3'UTR. The suppressive effect of miR-181d on MGMT expression was rescued by the introduction of an MGMT cDNA. Finally, MGMT expression inversely correlated with miR-181d expression in independent glioblastoma cohorts. Together, these results suggest that miR-181d is a predictive biomarker for TMZ response and that its role is mediated, in part, by posttranscriptional regulation of MGMT.
authors.affiliation: Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Katherine
authors.initials: K
authors.lastname: Hoadley
authors.forename: Deepa
authors.initials: D
authors.lastname: Kushwaha
authors.forename: Valya
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Shouwei
authors.initials: S
authors.lastname: Li
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
authors.forename: Chuanlu
authors.initials: C
authors.lastname: Jiang
authors.forename: Sonya Wei
authors.initials: SW
authors.lastname: Song
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D008156:Luciferases; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide