Previous studies reported that miR-433 exerts function widely in human tumorigenesis and development. Here, we further investigate the potential role of miR-433 in glioma. Quantitative real-time PCR demonstrated that miR-433-3p and miR-433-5p were low expressed in glioma tissues and cell lines. Functional studies suggested that the overexpression of miR-433-3p suppressed proliferation, induced apoptosis and inhibited invasion and migration of human glioma cells. But the growth and metastasis of glioma cells were not significantly influenced by overexpression of miR-433-5p. In a xenograft model, we also showed that miR-433-3p had an inhibitory effect on the growth of glioma. Bioinformatics coupled with luciferase and western blot assays revealed that CREB is a direct target of miR-433-3p, and the overexpression of CREB can rescue the phenotype changes induced by miR-433-3p overexpression. Besides, miR-433-3p could increase chemosensitivity of glioma to temozolomide by targeting CREB in vitro and in vivo. Taken together, these results suggest that miR-433-3p may function as a potential marker in diagnostic and therapeutic target for glioma.

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Abstract. Glioblastoma multiforme (GBM) is a prevalent and aggressive disease, and the development of a novel therapy to better treat advanced GBM is urgently required. Lactate dehydrogenase A (LDHA), which functions as a key enzyme in transforming pyruvate into lactate, has attracted more attention in recent years due to its critical role in various types of advanced cancer. Previous data derived from the Oncomine database have shown that the expression of LDHA is higher in GBM tissues than that in corresponding normal control tissues. However, the association of LDHA levels with glioma clinical grades and the possible mechanisms of LDHA in GBM progression have not been investigated. The present study showed that there is a significant positive correlation between LDHA expression levels and tumor clinical stages. The knockdown of LDHA inhibited cell growth by inhibiting cell cycle progression and inducing apoptosis in glioma cell lines. Upon investigating the molecular mechanism, LDHA knockdown via siRNA treatment was associated with decreased cyclin D1 expression, increased cleavage of PARP, and altered B-cell lymphoma 2 and B-cell lymphoma 2-associated protein X expression. In addition, LDHA knockdown led to the marked downregulation of matrix metalloproteinase (MMP)-2, MMP-9, VE-Cadherin and vascular endothelial growth factor expression levels. Furthermore, knock down of LDHA enhanced the chemosensitivity of glioma cells to temozolomide (TMZ), a second-generation alkylating agent with activity against recurrent high-grade glioma. These findings support LDHA as a novel target for developing effective therapeutic strategies to treat GBM.

Human riboflavin transporter 2 (RFT2) encoded by the SLC52A3 gene is a member of the SLC52 family that has been shown to play a key role in riboflavin homeostasis. Recently, a number of studies have shown that RFT2 is important in the development of several cancers, including esophageal squamous cell carcinoma, gastric cancer, and cervical cancer. However, its expression and function in glioma have not yet been explored. In this study, we found that RFT2 was overexpressed in glioma samples compared with normal brain tissue. Furthermore, RFT2 expression was correlated with WHO grade (P<0.001). Silencing of RFT2 resulted in inhibition of glioma cell proliferation through promotion of cell cycle arrest and apoptosis. Expression of proteins known to regulate cell cycle or apoptosis including p21, p27, BCL-2, and BAX was notably altered in RFT2-depleted cells. Furthermore, silencing of RFT2 impeded the migration and invasion of glioma cells through suppression of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression. In addition to blocking cell proliferation in vitro, reduction of RFT2 levels also decreased tumor growth in vivo. These data suggest that RFT2 could be an attractive therapeutic target for the treatment of glioma.