MiR-328 promotes glioma cell invasion via SFRP1-dependent Wnt-signaling activation

Abstract

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 protein 1 (SFRP1), an inhibitor 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.

ROBO3 promotes growth and metastasis of pancreatic carcinoma

“…Because SLIT-2/ROBO1 signaling has been shown to suppress cell invasion by repressing Wnt/β-catenin signaling (through β-catenin) [18], we hypothesized that ROBO3 might exert its oncogenic effect in pancreatic cancer by up-regulating Wnt/β-catenin signaling. In several human cancers, the silencing of negative regulators of Wnt signaling, such as SFRP1, enhances tumor cell invasiveness [21][22][23][24][25]. SFRP was first identified as an antagonist of Wnt signaling and regulator of apoptosis [26] and is believed to function as an extracellular Wnt inhibitor [27].…”

MiR-27a regulates Wnt/beta-catenin signaling through targeting SFRP1 in glioma

“…The Wnt/beta-catenin signaling pathway is constitutively activated in glioma [13,14]; aberrant expression of betacatenin in astrocytic gliomas and glioblastoma is linked to a higher tumor grade [14]. SFRP1, a member of Wnt inhibitors, is an extracellular signaling molecule that directly binds Wnt ligands and antagonizes the Wnt signaling pathway, and silence of SFRP1 enhances tumorigenicity [7,13,15].…”

“…SFRP1, a member of Wnt inhibitors, is an extracellular signaling molecule that directly binds Wnt ligands and antagonizes the Wnt signaling pathway, and silence of SFRP1 enhances tumorigenicity [7,13,15].…”

Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation

“…Transcription of miR-328-3p is found in many human tissues and has been shown to become de-regulated in different types of cancer [50], potentially affecting WNT-signaling via repression of the WNTinhibitor SFRP-1 [51]. Recently, it was shown that miR-328 targets the expression of CD44 in macrophages [52].…”