Abstract
Here, we report that microRNA-584-3p (miR-584-3p) is up-regulated in hypoxic glioma cells and in high-grade human glioma tumors (WHO grades III–IV) relative to normoxic cells and to low-grade tumors (WHO grades I–II), respectively. The postoperative survival time was significantly prolonged in the high-grade glioma patients with high miR-584-3p expression compared with those with low miR-584-3p expression. miR-584-3p may function as a potent tumor suppressor and as a prognostic biomarker for malignant glioma. However, the molecular mechanisms underlying these properties remain poorly understood. Our mechanistic studies revealed that miR-584-3p suppressed the migration and invasion of glioma cells by disrupting hypoxia-induced stress fiber formation. Specifically, we have found that ROCK1 is a direct and functionally relevant target of miR-584-3p in glioma cells. Our results have demonstrated a tumor suppressive function of miR-584-3p in glioma, in which it inhibits the migration and invasion of tumor cells by antagonizing hypoxia-induced, ROCK1-dependent stress fiber formation. Our findings have potential implications for glioma gene therapy and suggest that miR-584-3p could represent a prognostic indicator for glioma.
Highlights
Glioma, which is the most malignant tumor type, accounts for more than 70% of all brain tumors [1]
Because hypoxia is an independent prognostic factor for poor survival in glioma patients, we investigated the expression of hypoxia-induced miRNAs by performing high-throughput screening of all genomic miRNAs in normoxic and hypoxic U251 cells using a miRNA microarray, and we identified several targets with significantly increased expression under hypoxic conditions
We further verified the miR584–3p expression levels in hypoxic U251 and U87 cells by quantitative real-time PCR and found that the validated expression results were consistent with the microarray results. miR-584–3p expression peaked at approximately 24 h of hypoxia treatment in glioma cells (Figure 1D)
Summary
Glioma, which is the most malignant tumor type, accounts for more than 70% of all brain tumors [1]. The most common subtype of glioma is glioblastoma (GBM), with an age-adjusted incidence rate ranging from 0.59 to 3.69 per 100,000 persons [2]. The biological characteristics of GBM primarily include high mortality and recurrence rates [3], uncontrollable invasiveness [4], strong angiogenesis [5], and widespread hypoxia [6]. Tumor hypoxia is an independent prognostic factor for poor survival [6]. Numerous studies have suggested that hypoxia activates many cellular processes in tumors, such as proliferation, survival [7], angiogenesis [8], migration, and invasion [9]. Several mechanisms have been proposed to elucidate the hypoxia-induced migration and invasion of tumor cells, an increasing number of studies have evaluated the roles of highly expressed microRNAs (miRNAs) in mediating the effects of hypoxia
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