Recent evidence suggests that microRNAs (miRNAs) can be released to the extracellular microenvironment and mediate cell-cell communication through exosomes. The aim of this study was to identify exosomal miR-301a (exo-miR-301a) involved in glioblastoma (GBM) radioresistance and reveal the possible mechanisms. The exo-miR-301a specifically secreted by hypoxic GBM cells could transfer to corresponding normoxia-cultured cells and promote radiation resistance. Hypoxic exo-miR-301a directly targeted TCEAL7 genes, which were identified as a tumor suppressor in GBM malignancy and actively repressed its' expression in normoxic glioma cells. Our studies indicated that TCEAL7 negatively regulated the Wnt/ b-catenin pathway by blocking b-catenin translocation from cytoplasm to nucleus. Interestingly, we clarified that the Wnt/ b-catenin signaling was activated by miR-301a and TCEAL7 mediated the important procession. The exo-miR-301a was involved in the resistance to radiotherapy, and the effects would be reversed by miR-301a inhibition or TCEAL7 overexpression to regulate the Wnt/b-catenin axis. Here we show that exo-miR-301a, which is characteristically expressed and secreted by hypoxic glioma cells, is a potent regulator of Wnt/b-catenin and then depresses radiation sensitivity through targeting anti-oncogene TCEAL7. The newly identified exo-miR-301a/ TCEAL7-signaling axis could present a novel target for cellular resistance to cancer therapeutic radiation in GBM patients.

Our data indicate that serum exosomal miR-301a levels may reflect the cancer-bearing status and pathological changes in glioma patients. Serum exosomal miR-301a expression may serve as a novel biomarker for glioma diagnosis and as a prognostic factor for advanced grade disease.

G lioma is the most common primary intracranial tumor in adults, accounting for more than 40% of primary CNS neoplasms. In accordance with WHO classification, which is based on histomorphological criteria, gliomas are categorized as well-differentiated low-grade astrocytoma (WHO Grade I or II), anaplastic astrocytoma (WHO Grade III), or glioblastoma (GBM; WHO Grade IV). 15 The most frequent and malignant glioabbreviatioNs GBM = glioblastoma; KPS = Karnofsky Performance Scale; miR-205 = microRNA 205; miRNA = microRNA; OS = overall survival; PCNSL = primary diffuse large B-cell lymphoma of the CNS; qRT-PCR = quantitative reverse-transcription polymerase chain reaction. obJective Circulating microRNAs (miRNAs) are a new class of highly promising cancer biomarkers. Malignant glioma is one of the most devastating and lethal forms of intrinsic CNS tumor. Here, the authors evaluated serum miRNA 205 (miR-205) levels in patients with glioma. methods Sixty-four patients in whom glioma was diagnosed and 45 healthy controls were recruited between October 2011 and March 2012 and randomly assigned to the screening cohort or the validation cohort. Cohorts of patients with other brain tumors, including meningioma (n = 8), primary diffuse large B-cell lymphoma of the CNS (n = 6), and pituitary adenoma (n = 5), were investigated and compared. miR-205 extraction from serum was detected by real-time quantitative reverse-transcription polymerase chain reaction. The Kaplan-Meier method was applied to perform survival analysis, the risk factors were analyzed by using a Cox regression model, and the receiver operating characteristic working curve was used to analyze the value of miR-205 in the prognostic evaluation of the patients. results The authors first demonstrated that serum miR-205 expression was significantly lower in patients with glioma than in healthy controls (p < 0.001). It is important to note that serum miR-205 expression demonstrated a stepwise decrease with ascending pathological grades. The serum miR-205 biomarker had high sensitivity, specificity, and accuracy in patients with glioma. Serum levels of miR-205 were identified as an individual diagnostic marker and were significantly lower in the glioma cohort than in the other brain tumor cohorts. Serum miR-205 levels were significantly increased in postoperative samples over those in the preoperative samples and were reduced again during glioblastoma recurrences. Statistical analysis revealed a significant correlation between low serum miR-205 expression and both ascending pathological grades (p = 0.002) and low Karnofsky Performance Scale scores (p = 0.01). Patients with glioma at an advanced pathological grade (Grade III or IV) and a higher miR-205 serum level showed longer overall survival than those with a lower miR-205 serum concentration (p < 0.01). Furthermore, Cox regression analysis revealed that miR-205 serum levels were independently associated with overall survival. coNclusioNs These data indicate that serum miR-205 expression is a novel and valuable bioma...

These data provide compelling evidence that β-catenin regulation of miR-21 via STAT3 plays a role in glioma cell invasion and proliferation and indicate that STAT3 is a potential therapeutic target for glioma intervention.

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The study aimed to explore the specific function and mechanism of miR-144-3p in glioblastoma (GBM) cells with different phosphatase and tensin homolog (PTEN) phenotypes. We demonstrated that the miR-144-3p level was significantly down-regulated in glioma compared with the non-neoplastic brain tissues, and decreased with ascending grades. The loss of miR-144-3p effectively predicted the decreased overall survival in glioma patients. Interestingly, the expression of MET was up-regulated and inversely associated with miR-144-3p level in glioma tissues. Next, we certified that miR-144-3p specifically bound to MET 3 0 -untranslated region (3 0 UTR) and inhibited its expression. miR-144-3p potently repressed GBM cell proliferation and invasion via suppressing MET in vitro and in vivo. In addition, our results showed no difference in malignancy inhibition induced by miR-144-3p in GBM cells with different PTEN phenotypes. miR-144-3p inhibited several survival signaling pathways by targeting MET independent of PTEN status in GBM cells. Overexpression of miR-144-3p inhibited survival capability and increased apoptosis, resulting in enhancement of radiation and temozolomide sensitivity. Our data provide new insights into the potential application of miR-144-3p in GBM therapy by targeting MET and then inhibiting the downstream signaling.

Temozolomide (TMZ) has been widely used in the treatment of glioblastoma (GBM), although inherent or acquired resistance restricts the application. This study was aimed to evaluate the efficacy of sulforaphane (SFN) to TMZ-induced apoptosis in GBM cells and the potential mechanism. Biochemical assays and subcutaneous tumor establishment were used to characterize the function of SFN in TMZ-induced apoptosis. Our results revealed that b-catenin and miR-21 were concordantly expressed in GBM cell lines, and SFN significantly reduced miR-21 expression through inhibiting the Wnt/b-catenin/TCF4 pathway. Furthermore, down-regulation of miR-21 enhanced the pro-apoptotic efficacy of TMZ in GBM cells. Finally, we observed that SFN strengthened TMZ-mediated apoptosis in a miR-21-dependent manner. In conclusion, SFN effectively enhances TMZ-induced apoptosis by inhibiting miR-21 via Wnt/b-catenin signaling in GBM cells. These findings support the use of SFN for potential therapeutic approach to overcome TMZ resistance in GBM treatment.

Our findings indicate that miR-21 regulates hTERT expression mediated by STAT3, therefore controlling GBM cell growth.