TY - JOUR
T1 - miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma
AU - Khalil, Susanna
AU - Fabbri, Enrica
AU - Santangelo, Alessandra
AU - Bezzerri, Valentino
AU - Cantù, Cinzia
AU - Di Gennaro, Gianfranco
AU - Finotti, Alessia
AU - Ghimenton, Claudio
AU - Eccher, Albino
AU - Dechecchi, Maria
AU - Scarpa, Aldo
AU - Hirshman, Brian
AU - Chen, Clark
AU - Ferracin, Manuela
AU - Negrini, Massimo
AU - Gambari, Roberto
AU - Cabrini, Giulio
PY - 2016/5/10
Y1 - 2016/5/10
N2 - The levels of expression of O6-methylguanine-DNA methyltransferase (MGMT) are relevant in predicting the response to the alkylating chemotherapy in patients affected by glioblastoma. MGMT promoter methylation and the published MGMT regulating microRNAs (miRNAs) do not completely explain the expression pattern of MGMT in clinical glioblastoma specimens. Here we used a genome-wide microarraybased approach to identify MGMT regulating miRNAs. Our screen unveiled three novel MGMT regulating miRNAs, miR-127-3p, miR-409-3p, and miR-124-3p, in addition to the previously identified miR-181d-5p. Transfection of these three novel miRNAs into the T98G glioblastoma cell line suppressed MGMT mRNA and protein expression. However, their MGMT-suppressive effects are 30-50% relative that seen with miR-181d-5p transfection. In silico analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) revealed that miR-181d-5p is the only miRNA that consistently exhibited inverse correlation with MGMT mRNA expression. However, statistical models incorporating both miR-181d-5p and miR-409-3p expression better predict MGMT expression relative to models involving either miRNA alone. Our results confirmed miR-181d-5p as the key MGMT-regulating miRNA. Other MGMT regulating miRNAs, including the miR-409-3p identified in this report, modify the effect of miR-181d-5p on MGMT expression. MGMT expression is, thus, regulated by cooperative interaction between key MGMT-regulating miRNAs.
AB - The levels of expression of O6-methylguanine-DNA methyltransferase (MGMT) are relevant in predicting the response to the alkylating chemotherapy in patients affected by glioblastoma. MGMT promoter methylation and the published MGMT regulating microRNAs (miRNAs) do not completely explain the expression pattern of MGMT in clinical glioblastoma specimens. Here we used a genome-wide microarraybased approach to identify MGMT regulating miRNAs. Our screen unveiled three novel MGMT regulating miRNAs, miR-127-3p, miR-409-3p, and miR-124-3p, in addition to the previously identified miR-181d-5p. Transfection of these three novel miRNAs into the T98G glioblastoma cell line suppressed MGMT mRNA and protein expression. However, their MGMT-suppressive effects are 30-50% relative that seen with miR-181d-5p transfection. In silico analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) revealed that miR-181d-5p is the only miRNA that consistently exhibited inverse correlation with MGMT mRNA expression. However, statistical models incorporating both miR-181d-5p and miR-409-3p expression better predict MGMT expression relative to models involving either miRNA alone. Our results confirmed miR-181d-5p as the key MGMT-regulating miRNA. Other MGMT regulating miRNAs, including the miR-409-3p identified in this report, modify the effect of miR-181d-5p on MGMT expression. MGMT expression is, thus, regulated by cooperative interaction between key MGMT-regulating miRNAs.
KW - Glioblastoma
KW - MGMT
KW - MiR-181d-5p
KW - MiR-409-3p
UR - http://www.scopus.com/inward/record.url?scp=84968779606&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84968779606&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.8618
DO - 10.18632/oncotarget.8618
M3 - Article
C2 - 27057640
AN - SCOPUS:84968779606
VL - 7
SP - 28195
EP - 28206
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 19
ER -