Abstract
MicroRNA128-1 (miR128-1), as a brain-specific miRNA, is downregulated in glioblastoma multiforme (GBM) and closely associated with the progression of GBM. However, the underlying molecular mechanism of the downregulation and its role in the regulation of tumorigenesis and anticancer drug resistance in GBM remains largely unknown. In the current study,we found that miR128-1 was downregulated in GBM and glioma stem-like cells (GSCs). Intriguingly, treatment with the DNA methylation inhibitors 5-Aza-CdR (Aza) and 4-phenylbutyric acid (PBA) resulted in miR128-1 upregulation in both GBM cells and GSCs. Either forced expression of miR128-1 or Aza/PBA treatment inhibited tumor cell proliferation, migration and invasion in vitro. Moreover, overexpression of miR128-1 inhibited the growth of transplant tumor in vivo. BMI1 and E2F3 were found to be direct targets of miR128-1 and downregulated by miR128-1 in vitro and in vivo. Our results revealed a mechanism of methylation that controls miR128-1 expression in GBM cells and GSCs and indicate miR128-1 could function as a tumor suppressor in GBM by negatively regulating tumor cell proliferation, invasion and self-renewal through direct targeting BMI1 and E2F3. Our findings suggest that DNA methylation inhibitors are potential agents for GBM treatment by upregulating miR-128-1.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults and approximately 20,000 new cases are diagnosed in the United States every year
We demonstrated miR128-1 was downregulated in glioma cells and their glioma stem-like cells (GSCs) when compared with normal brain tissues; the miR128-1 level in GSCs was restively higher than the corresponding parental glioma cells
We showed that miR128-1 targeted BMI1 and E2F3, and miR128-1 overexpression down-regulated BMI1 and E2F3 in glioblastoma cells both in vitro and in mouse tumor xenografts
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults and approximately 20,000 new cases are diagnosed in the United States every year. Significant advances have been made in the treatment of GBM; even with aggressive systematic surgery, radiation and chemotherapy, the median survival of GBM patients remains shorter than 15 months [1]. Mounting evidence has shown that glioblastoma cells retain features of neural progenitor cells, including self-renewal and the ability to grow as neurospheres in culture [2, 3]. This subpopulation of tumor cells is known as glioma stem-like cells (GSCs) and believed to give rise to the heterogeneity of GBM cancer cells and contribute to the resistance to currently available antitumor therapies. The precise mechanism of the regulation of the proliferation, survival and maintenance of GSCs remains elusive
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