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Inactivated LRRC4 has been clinically detected in gliomas, and promoter hypermethylation has been implicated as the mechanism of inactivation in some of those tumors. Our previous researches indicated that LRRC4 is a target gene of miR-381, the interaction of miR-381 and LRRC4 is involved in glioma growth. In this study, we demonstrate that LRRC4 is a target gene of the other microRNA, miR-182. We found that the high expression of miR-182 and miR-381 in gliomas are involved in pathological malignant progression. The silencing of miR-182 and miR-381 inhibited the proliferation in vitro and growth of glioma cell with in vivo magnetic resonance imaging by intracranial transplanted tumor model in rats. We also demonstrated that BRD7, a transcriptional cofactor for p53, is highly expressed and negatively correlated with LRRC4 expression in gliomas. Disturbing miR-182 and miR-381 affected transcriptional regulation of the BRD7 gene. This finding was verified by ectopic overexpression of LRRC4 or restoration of endogenous LRRC4 expression by treatment with the DNA demethylating agent 5-Aza-dC. Taken together, miR-182 and miR-381 may be a useful therapeutic target for treatment of glioma. [ABSTRACT FROM AUTHOR]

Abstract: LRRC4 is not only a brain-specific gene, but it has also been identified as a tumor suppressor gene for glioma. Promoter methylation of LRRC4 is frequently involved in the inactivation in glioma. MiRNA-mediated gene regulation has recently been demonstrated to play an important role in multiple biological processes related to cancer, including glioma. In this study, we demonstrated that a small regulatory microRNA, hsa-miR-381, an “oncomir”, had a major role in glioma progression and that LRRC4 was a target of hsa-miR-381. By regulating LRRC4, hsa-miR-381 increased the in vitro and in vivo proliferation of glioma cells, and this action was associated with decreased inhibition of MEK/ERK and AKT signaling. Conversely, LRRC4, as a glioma suppressor, inhibited the endogenous expression of hsa-miR-381 and decreased cell proliferation and tumor growth. The interaction of hsa-miR-381 and LRRC4 is involved in the pathogenesis of glioma. In addition, the stable expression of hsa-miR-381 in blood provides a novel and promising diagnostic biomarker, and anti-hsa-miR-381 “antagomir” may be an ideal target for glioma therapy. [Copyright &y& Elsevier]

Abstract: POTE ankyrin domain family, member H (POTEH) belongs to POTE family, which expresses in many cancers. In this study, methylation status of POTEH promoter and its correlation with clinicopathological parameters were evaluated in glioma tissues and cells. Bisulfite sequencing PCR was carried out to investigate the promoter methylation status of POTEH in tumor of 96 glioma patients and glioma cells U251, SF767, and SF126. The effect of promoter hypomethylation on protein expression was evaluated by immunohistochemistry. POTEH was hypomethylated in 81.3% gliomas and none in normal brain tissues, and correlated significantly with its protein expression. But there was no remarkable relationship between sex, age, advanced tumor grade and POTEH hypomethylation. With the grade progressing, POTEH protein expression was enhanced. The correlation between POTEH hypomethylation, protein expression and overall survival was statistically significant. In POTEH hypomethylation group, patients with POTEH high expression had shorter overall survival than those with low expression. Hypomethylation of POTEH promoter in gliomas accounted for POTEH protein overexpression and poor outcome in a subset of patients. Detection of these epigenetic changes in tumors may provide information regarding prognosis. [Copyright &y& Elsevier]