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Expression level of miRNAs on chromosome 14q32.31 region correlates with tumor aggressiveness and survival of glioblastoma patients

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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.

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    Authors and Affiliations

    1. Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel

      Tal Shahar & Zvi Ram

    2. The Laboratory for Molecular Neuro-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel

      Tal Shahar & Zvi Ram

    3. Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel

      Avital Granit, Daniel Zrihan, Tamar Canello, Hanna Charbit, Ofira Einstein & Iris Lavon

    4. Physiotherapy Department, Ariel University, Ariel, Israel

      Ofira Einstein

    5. Division of Hematology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, Petach Tikva, Israel

      Uri Rozovski

    6. Tel Aviv University, Tel Aviv, Israel

      Uri Rozovski & Zvi Ram

    7. Info-CORE, Bioinformatics Unit of the I-CORE Computation Center, Hadassah, Hebrew University medical center, Jerusalem, Israel

      Sharona Elgavish

    8. Center for Neuro-Oncology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, Petach Tikva, Israel

      Tali Siegal

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    Tal Shahar, Avital Granit, Zvi Ram, Tali Siegal and Iris Lavon have contributed equally to the work.

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    Shahar, T., Granit, A., Zrihan, D. et al. Expression level of miRNAs on chromosome 14q32.31 region correlates with tumor aggressiveness and survival of glioblastoma patients. J Neurooncol 130, 413–422 (2016). https://doi.org/10.1007/s11060-016-2248-0

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