BACKGROUND:The coiled-coil domain is a structural motif found in proteins that participate in a variety of biological processes. Aberrant expression of such proteins has been shown to be associated with the malignant behavior of human cancers. In this study, we investigated the role of a specific family member, coiled-coil domain containing 109B (CCDC109B), in human gliomas. METHODS AND RESULTS:We confirmed that CCDC109B was highly expressed in high grade gliomas (HGG; WHO III-IV) using immunofluorescence, western blot analysis, immunohistochemistry (IHC) and open databases. Through Cox regression analysis of The Cancer Genome Atlas (TCGA) database, we found that the expression levels of CCDC109B were inversely correlated with patient overall survival and it could serve as a prognostic marker. Then, a serious of cell functional assays were performed in human glioma cell lines, U87MG and U251, which indicated that silencing of CCDC109B attenuated glioma proliferation and migration/invasion both in vitro and in vivo. Notably, IHC staining in primary glioma samples interestingly revealed localization of elevated CCDC109B expression in necrotic areas which are typically hypoxic. Moreover, small interfering RNA (siRNA) and specific inhibiters of HIF1α led to decreased expression of CCDC109B in vitro and in vivo. Transwell assay further showed that CCDC109B is a critical factor in mediating HIF1α-induced glioma cell migration and invasion. CONCLUSION:Our study elucidated a role for CCDC109B as an oncogene and a prognostic marker in human gliomas. CCDC109B may provide a novel therapeutic target for the treatment of human glioma.

译文

背景:卷曲螺旋结构域是在参与多种生物学过程的蛋白质中发现的结构基序。已经表明这种蛋白质的异常表达与人类癌症的恶性行为有关。在这项研究中,我们调查了一个特定的家庭成员,包含109B(CCDC109B)的卷曲螺旋域在人类神经胶质瘤中的作用。
方法和结果:我们使用免疫荧光,免疫印迹分析,免疫组化(IHC)和开放式数据库证实了CCDC109B在高级别胶质瘤(HGG; WHO III-IV)中高表达。通过癌症基因组图谱(TCGA)数据库的Cox回归分析,我们发现CCDC109B的表达水平与患者的总体生存率呈负相关,并且可以作为预后的标志物。然后,在人神经胶质瘤细胞系U87MG和U251中进行了严重的细胞功能测定,这表明CCDC109B的沉默在体外和体内均减弱了神经胶质瘤的增殖和迁移/侵袭。值得注意的是,原发性神经胶质瘤样本中的IHC染色有趣地揭示了在通常缺氧的坏死区域中CCDC109B表达升高的定位。此外,小的干扰RNA(siRNA)和HIF1α的特异性抑制剂导致CCDC109B在体外和体内的表达降低。 Transwell分析进一步表明,CCDC109B是介导HIF1α诱导的神经胶质瘤细胞迁移和侵袭的关键因素。
结论:我们的研究阐明了CCDC109B在人类神经胶质瘤中作为癌基因和预后标志物的作用。 CCDC109B可为治疗人脑胶质瘤提供新的治疗靶标。

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