title: Expression level of miRNAs on chromosome 14q32.31 region correlates with tumor aggressiveness and survival of glioblastoma patients.
abstract: The 54 microRNAs (miRNAs) within the DLK-DIO3 genomic region on chromosome 14q32.31 (cluster-14-miRNAs) are organized into sub-clusters 14A and 14B. These miRNAs are downregulated in glioblastomas and might have a tumor suppressive role. Any association between the expression levels of cluster-14-miRNAs with overall survival (OS) is undetermined. We randomly selected miR-433, belonging to sub-cluster 14A and miR-323a-3p and miR-369-3p, belonging to sub-cluster 14B, and assessed their role in glioblastomas in vitro and in vivo. We also determined the expression level of cluster-14-miRNAs in 27 patients with newly diagnosed glioblastoma, and analyzed the association between their level of expression and OS. Overexpression of miR-323a-3p and miR-369-3p, but not miR-433, in glioblastoma cells inhibited their proliferation and migration in vitro. Mice implanted with glioblastoma cells overexpressing miR323a-3p and miR369-3p, but not miR433, exhibited prolonged survival compared to controls (P = .003). Bioinformatics analysis identified 13 putative target genes of cluster-14-miRNAs, and real-time RT-PCR validated these findings. Pathway analysis of the putative target genes identified neuregulin as the most enriched pathway. The expression level of cluster-14-miRNAs correlated with patients' OS. The median OS was 8.5 months for patients with low expression levels and 52.7 months for patients with high expression levels (HR 0.34; 95 % CI 0.12-0.59, P = .003). The expression level of cluster-14-miRNAs correlates directly with OS, suggesting a role for this cluster in promoting aggressive behavior of glioblastoma, possibly through ErBb/neuregulin signaling.
authors: Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel.|The Laboratory for Molecular Neuro-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Tal
authors: T
authors: Shahar
authors: Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Avital
authors: A
authors: Granit
authors: Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Daniel
authors: D
authors: Zrihan
authors: Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Tamar
authors: T
authors: Canello
authors: Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Hanna
authors: H
authors: Charbit
authors: Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.|Physiotherapy Department, Ariel University, Ariel, Israel.
authors: Ofira
authors: O
authors: Einstein
authors: Division of Hematology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, Petach Tikva, Israel.|Tel Aviv University, Tel Aviv, Israel.
authors: Uri
authors: U
authors: Rozovski
authors: Info-CORE, Bioinformatics Unit of the I-CORE Computation Center, Hadassah, Hebrew University medical center, Jerusalem, Israel.
authors: Sharona
authors: S
authors: Elgavish
authors: Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel.|The Laboratory for Molecular Neuro-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel.|Tel Aviv University, Tel Aviv, Israel.
authors: Zvi
authors: Z
authors: Ram
authors: Center for Neuro-Oncology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, Petach Tikva, Israel.
authors: Tali
authors: T
authors: Siegal
authors: Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel. IrisL@Hadassah.org.il.
authors: Iris
authors: 0000-0002-6526-1573
authors: I
authors: Lavon
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002883:Chromosomes, Human, Pair 14; D015331:Cohort Studies; D019295:Computational Biology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D016019:Survival Analysis; D014162:Transfection
chemical_list: D035683:MicroRNAs
keywords: Chromosome 14q32.31; Glioblastoma; Neuregulin; miRNAs