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Temozolomide (TMZ) is a promising chemotherapeutic agent to treat Glioblastoma multiforme (GBM). However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells' resistance to TMZ are not fully understood. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. Recently, miRNAs have been discovered to play important roles in drug resistance. A previous study showed that miR-181b in involved in glioma tumorigenesis. Thus, it would be valuable to explore the functions and mechanisms of miR-181b in regulating GMB cells' sensitivity to TMZ. In this study, quantitative real-time reverse transcription PCR (qRT-PCR) data indicated that miR-181b was significantly downregulated in recurrent GBM tissues compared with initial GBM tissues. We also found that miR-181b overexpression increased the chemo-sensitivity of GBM cells to TMZ and potentiated TMZ-induced apoptosis in vitro and in vivo. Moreover, we demonstrated that the epidermal growth factor receptor (EGFR) was a direct target of miR-181b: restoration of EGFR rescued the inhibitory effects of miR-181b and TMZ treatment. Taken together, our data support strongly an important role for miR-181b in conferring TMZ resistance by targeting EGFR expression. [ABSTRACT FROM AUTHOR]

Glioblastoma is one of the most frequent and aggressive brain tumors. Accumulating evidence indicates that microRNAs are involved in glioma proliferation, invasion and drug resistance. Previous studies showed that miR-198 is downregulated in glioblastoma. However, the function of miR-198 in glioblastoma is still unclear. In this study, we report that miR-198 levels were greatly downregulated in glioblastoma specimens and decreased expression of miR-198 was associated with poor prognosis in patients with glioblastoma. And overexpression of miR-198 increased chemosensitivity to temozolomide in vitro and in vivo. O-methylguanine-DNA methyltransferase (MGMT) was identified as a direct target of miR-198, and miR-198 overexpression prevented the protein translation of MGMT. Furthermore, overexpression of MGMT restored miR-198-induced chemosensitivity to temozolomide. Moreover, the protein levels of MGMT were upregulated in clinical glioblastoma specimens and inversely correlated with miR-198 levels. In conclusion, our studies revealed that MiR-198 induces chemosensitivity in glioblastoma by targeting MGMT and that miR-198 may be used as a new diagnostic marker and therapeutic target for glioblastoma in the future. [ABSTRACT FROM AUTHOR]

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin −31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin −31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin −31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations. [ABSTRACT FROM AUTHOR]

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance. [ABSTRACT FROM AUTHOR]