MicroRNA-218 Inhibits Glioma Invasion, Migration, Proliferation, and Cancer Stem-like Cell Self-Renewal by Targeting the Polycomb Group Gene Bmi1

Abstract

Malignant gliomas are the most common central nervous system tumors and the molecular mechanism driving their development and recurrence is still largely unknown, limiting the treatment of this disease. Here, we show that restoring the expression of miR-218, a microRNA commonly downregulated in glioma, dramatically reduces the migration, invasion, and proliferation of glioma cells. Quantitative reverse transcription PCR and Western blotting analysis revealed that expression of the stem cell-promoting oncogene Bmi1 was decreased after overexpression of miR-218 in glioma cells. Mechanistic investigations defined Bmi1 as a functional downstream target of miR-218 through which miR-218 ablated cell migration and proliferation. We documented that miR-218 also blocked the self-renewal of glioma stem-like cells, consistent with the suggested role of Bmi1 in stem cell growth. Finally, we showed that miR-218 regulated a broad range of genes involved in glioma cell development, including Wnt pathways that suppress glioma cell stem-like qualities. Taken together, our findings reveal miR-218 as a tumor suppressor that prevents migration, invasion, proliferation, and stemlike qualities in glioma cells. Cancer Res; 73(19); 6046-55. Ó2013 AACR.

Downregulation of Pygopus 2 inhibits vascular mimicry in glioma U251 cells by suppressing the canonical Wnt signaling pathway

“…Glioma is a diffuse and highly-invasive tumor, resulting in a dismal prognosis, and long-term survivors are rare (3). Gliomas are also characterized by high migratory and proliferative abilities (4). However, the molecular mechanism that triggers the development of gliomas is elusive and requires additional investigation.…”

MicroRNA-873 (MiRNA-873) Inhibits Glioblastoma Tumorigenesis and Metastasis by Suppressing the Expression of IGF2BP1

“…For instance, miR-21 acts as an antiapoptotic factor in GBM by targeting the p53 network (8 -10); miR-10b is involved in the cell cycle and programmed cell death via regulating the expression of Bim, TFAP2C, p16, and p21 (11); miR-218 inhibits cell migration, invasion, proliferation, and stem-like qualities by targeting Bmi1 (12); miR-195 negatively regulates the proliferation of glioma cells by down-regulating the expression of cyclin D1 and cyclin E1 (13); miR-137 inhibits the growth of glioma cells by directly targeting Rac1 (14); and miR-16 functions as a tumor suppressor gene in glioma growth and invasiveness via the inhibition of BCL2 and the NF-KB1/MMP-9 signaling pathway (15). All of these miRNAs play important roles in the development of the malignant GBM phenotype.…”

Expression of microRNA-218 and its Clinicopathological and Prognostic Significance in Human Glioma Cases

“…Interestingly, tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer (Nishikawa et al, 2014). It was also found that miR-218 could inhibit migration and invasion in other human cancers by targeting multiple mRNAs, including glioma (Yamamoto et al, 2013;Yamasaki et al, 2013;Tu et al, 2013). The emerging role of tumor-suppressive microRNA-218 in targeting glioblastoma stemness is also reported (Gao X and Jin W, 2014).…”

“…Recently, microRNA-218 (miR-218) has been reported to serve as a tumor suppressor in numerous types of cancer by regulation of the expression of target genes. In glioma, miR-218 could inhibit glioma invasion, migration, proliferation, and cancer stem-like cell selfrenewal by targeting the polycomb group gene Bmi1 (Tu et al, 2013). Also, miR-218 acts as a tumor suppressor by targeting multiple cancer phenotype-associated genes in medulloblastoma (Venkataraman et al, 2013).…”