Recent studies have shown that isocitrate dehydrogenase1 ⁄ 2 (IDH1 ⁄ 2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression-free survival and overall survival. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58 ⁄ 79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression-free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma. (Cancer Sci 2012; 103: 269-273) G lioblastomas (GBMs), the most common and malignant primary brain tumors in adults, may develop rapidly after a short history and without evidence of less malignant precursor lesions (primary GBM, pGBM), or through progression from low-grade or anaplastic gliomas (secondary GBM, sGBM).(1-3)In GBM, the clinical value of O(6)-methylguanine DNA methyltransferase (MGMT) promotor methylation status in predicting benefit from alkylating agents has been validated by several clinical trials, both in patients treated with nitrosourea and in those with temozolomide (TMZ). (4,5) In the European Organization for Research and Treatment of Cancer (EORTC) ⁄ National Cancer Institute of Canada (NCIC) 26981 ⁄ 22981 trial evaluating the effect of radiotherapy plus concomitant and adjuvant TMZ versus radiotherapy alone in GBM, methylation of MGMT promotor emerged as the strongest predictor for outcome and benefit from chemotherapy.(6,7) However, all of these studies were based on newly diagnosed GBMs, most of which were pGBMs. So far, there is no clear evidence that MGMT promotor methylation plays the same role in sGBMs, as these two subtypes constitute distinct disease entities and develop through different genetic pathways. (2,3,8) In 2008, a genome-wide sequencing study identified somatic mutations on codon 132 in a gene encoding isocitrate dehydrogenase-1 (IDH1) in 12% s...

Accumulating evidence has implied that microRNAs (miRNAs) are implicated in glioma progression, and genetically engineered mesenchymal stem cells can help to inhibit tumor growth of glioma. Herein we hypothesized that miR-199a could be delivered by mesenchymal stem cells to glioma cells through exosomes and thus prevent the glioma development by down-regulating ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 (AGAP2). The expression pattern of miR-199a and AGAP2 was characterized in glioma tissues and cells using RNA polymerase chain reaction quantification, immunohistochemical staining and Western blot assays. Mesenchymal stem cells transfected with miR-199a mimic or their derived exosomes were co-cultured with U251 cells. The biological behaviors as well as chemosensitivity of U251 cells were assessed to explore the involvement of miR-199a/AGAP2 in glioma. MiR-199a was poorly expressed in glioma tissue and cells while AGAP2 was highly expressed. Mesenchymal stem cells delivered miR-199a to the glioma cells via the exosomes, which resulted in the suppression of the proliferation, invasion and migration of glioma cells. Besides, mesenchymal stem cells over-expressing miR-199a enhanced the chemosensitivity to temozolomide and inhibited the tumor growth in vivo . Taken together, mesenchymal stem cell-derived exosomal miR-199a can inhibit the progression of glioma by down-regulating AGAP2.

Objective: Long non-coding RNAs have been demonstrated to be involved in the progression of a variety of cancers, including glioma. Through microarray analyses, long intergenic non-protein coding RNA 00475 (LINC00475) was identified in the glioma development. However, its potential role remains incompletely understood. This study aimed to elucidate the effect of LINC00475 on the development of glioma under hypoxic conditions. Methods: Glioma cells underwent hypoxic treatment and were collected. The functional role of LINC00475 and AGAP2 in glioma was determined using ectopic expression, depletion, and reporter assay experiments. Then, the expression of LINC00475, microRNA (miR)-449b-5p, AGAP2, FAK, and HIF-1α was determined. In addition, cell migration and invasion were examined. Finally, a tumor xenograft was carried out in nude mice to explore the role of LINC00475 on oxidation in vivo. Results: LINC00475 was identified to be overexpressed in hypoxic glioma samples, which was further observed to bind to and down-regulate miR-449b-5p, and negatively targeted AGAP2. Moreover, we also revealed a positive correlation between LINC00475 and AGAP2 expression in glioma. In addition, silencing of LINC00475 decreased the extent of FAK phosphorylation and reduced the expression of HIF-1α and AGAP2. It was also observed that LINC00475 silencing suppressed glioma cell proliferation, migration, and invasion, and promoted cell apoptosis. Moreover, oxidation of nude mice was promoted by LINC00475 silencing. Conclusion: Taken together, LINC00475 silencing exerted an inhibitory effect on glioma under hypoxic conditions by down-regulating AGAP2 via up-regulation of miR-449b-5p.

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