MiR-328 promotes glioma cell invasion via SFRP1-dependent Wnt-signaling activation
MiR-328 promotes glioma cell invasion via SFRP1-dependent Wnt-signaling activation
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DOI：
10.1093/neuonc/not164
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发表时间：
2014-02-01
期刊：
影响因子：
15.9
通讯作者：
Riemenschneider, Markus J.
中科院分区：
文献类型：
--
作者：
Delic, Sabit;Lottmann, Nadine;Riemenschneider, Markus J.
背景星形胶质细胞瘤的弥漫浸润性生长是肿瘤治疗成功的主要障碍之一。因此，深入了解神经胶质瘤细胞侵袭的分子和信号通路对于靶向和个体化治疗的发展具有重要意义。通过对显微切割的人类肿瘤活检标本的miRNA表达谱分析，我们鉴定了miR-328是在体内侵袭胶质瘤细胞中上调的主要miRNA之一，并进一步研究了其在胶质瘤发病机制中的作用。我们使用miRNA模拟物和抑制剂来功能性地表征miR-328，使用3 '非翻译区荧光素酶分析和T细胞因子/淋巴增强因子报告基因分析来确定miR-328的靶点和信号通路，并分析了miR-328在一个大的神经胶质瘤组中的表达。首先，我们证实了miR-328在A172和TP 365 MG胶质瘤细胞中的侵袭促进作用。分泌型卷曲相关蛋白1（SFRP 1），Wnt信号的抑制剂，被确定为miR-328的直接靶点。SFRP 1表达在表达降低的胶质瘤中具有预后相关性，在分子脑肿瘤数据库（REMBRANDT）和癌症基因组图谱中与显著较低的总体患者存活率相关。值得注意的是，miR-328调节SFRP 1蛋白表达水平和Wnt信号通路活性。最后，在人脑胶质瘤组织中，miR-328似乎优先在低级别星形细胞胶质瘤中解释SFRP 1的下调，并且与SFRP 1启动子高甲基化呈负相关。总之，我们报告了一种新的分子miR-328依赖性机制，通过SFRP 1抑制和Wnt激活有助于在胶质瘤进展的早期阶段的浸润性胶质瘤表型，对疾病的最终结局具有不利的预后意义。
Background. Diffusely infiltrative growth of human astrocytic gliomas is one of the major obstacles to successful tumor therapy. Thorough insights into the molecules and pathways signaling glioma cell invasion thus appear of major relevance for the development of targeted and individualized therapies. By miRNA expression profiling of microdissected human tumor biopsy specimens we identified miR-328 as one of the main miRNAs upregulated in invading glioma cells in vivo and further investigated its role in glioma pathogenesis.Methods. We employed miRNA mimics and inhibitors to functionally characterize miR-328, 3' untranslated region luciferase assays, and T-cell factor/lymphoid enhancer factor reporter assays to pinpoint miR-328 targets and signaling pathways, and analyzed miR-328 expression in a large panel of gliomas.Results. First, we corroborated the invasion-promoting role of miR-328 in A172 and TP365MG glioma cells. Secreted Frizzled-related protein1(SFRP1), aninhibitor of Wnt signaling, was then pinpointed as a direct miR-328 target. SFRP1 expression is of prognostic relevance in gliomas with reduced expression, being associated with significantly lower overall patient survival in both the Repository of Molecular Brain Neoplasia Data (REMBRANDT) and The Cancer Genome Atlas. Of note, miR-328 regulated both SFRP1 protein expression levels and Wnt signaling pathway activity. Finally, in human glioma tissues miR-328 appeared to account for the downregulation of SFRP1 preferentially in lower-grade astrocytic gliomas and was inversely related to SFRP1 promoter hypermethylation.Conclusion. Taken together, we report on a novel molecular miR-328-dependent mechanism that via SFRP1 inhibition and Wnt activation contributes to the infiltrative glioma phenotype at already early stages of glioma progression, with unfavorable prognostic implications for the final outcome of the disease.