MiR-181d: Predictive glioblastoma biomarker that downregulates MGMT expression

Wei Zhang, Jing Zhang, Katherine Hoadley, Deepa Kushwaha, Valya Ramakrishnan, Shouwei Li, Chunsheng Kang, Yongping You, Chuanlu Jiang, Sonya Wei Song, Tao Jiang, Clark C. Chen

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

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 3UTR. 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.

Original languageEnglish (US)
Pages (from-to)712-719
Number of pages8
JournalNeuro-Oncology
Volume14
Issue number6
DOIs
StatePublished - Jun 2012

Keywords

  • MGMT
  • biomarker
  • glioblastoma
  • miR-181d
  • temozolomide

Fingerprint

Dive into the research topics of 'MiR-181d: Predictive glioblastoma biomarker that downregulates MGMT expression'. Together they form a unique fingerprint.

Cite this