MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1
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Ariel Bier,1 Nis Giladi,1 Noam Kronfeld,1 Hae Kyung Lee,2 Simona Cazacu,2 Susan Finniss,2 Cunli Xiang,2 Laila Poisson,3 Ana C. deCarvalho2, Shimon Slavin4, Elad Jacoby,5 Michal Yalon,5 Amos Toren,5 Tom Mikkelsen2 and Chaya Brodie1,2
1 Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel,
2 Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit MI USA.
3 Department of Public Health Sciences, Tel Aviv, Israel
4 The International Center for Cell Therapy and Cancer Immunotherapy (CTCI), Tel Aviv, Israel,
5 Pediatric Hemato-Oncology, The Edmond and Lilly Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer and The Sackler School of Medicine, Tel-Aviv University, Israel.
Chaya Brodie, email:
Keywords: Glioma stem cells, self renewal, miR-137, RTVP-1, CXCR4
Received: March 12, 2013 Accepted: April 7, 2013 Published: April 9, 2013
Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3’-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3’-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.
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