Dataset Information

Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/?-catenin signaling through downregulating SOX7.

ABSTRACT: Long noncoding RNA (lncRNA) AB073614 has recently shown to be aberrantly increased and identified as a poor prognostic biomarker in human glioma. However, the potential mechanisms remain unknown. This study demonstrated that AB073614 expression was significantly upregulated in both glioma tissues and cell lines, and glioma patients with high AB073614 expression had lower overall survival rates. Importantly, silencing AB073614 expression remarkably inhibited U251 cell proliferation, migration, and invasion in vitro, as well as suppressed tumor formation in vivo. The level of AB073614 was found to correlate inversely with sex-determining region Y-box 7 (SOX7) expression but correlate positively with Wnt/?-catenin signaling activity. Of note, the data showed that the inhibition of SOX7 could reverse the tumor-suppressive effect of the silencing AB073614 on glioma in vitro and in vivo. Furthermore, the results indicated that AB073614 induced Wnt/?-catenin signaling activity by repressing SOX7 expression. In conclusion, the findings demonstrated that AB073614 promoted the progression of glioma by targeting SOX7 to activate the Wnt/?-catenin signaling pathway, suggesting that the inhibition of AB073614 might be a potential target for therapeutic intervention in glioma patients.

SUBMITTER: Li Y

PROVIDER: S-EPMC5630354 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/β-catenin signaling through downregulating SOX7.

Li Yuqian Y Zhu Gang G Zeng Wen W Wang Jiancai J Li Zhihong Z Wang Bao B Tian Bo B Lu Dan D Zhang Xingye X Gao Guodong G Li Lihong L

Oncotarget 20170717 39

Long noncoding RNA (lncRNA) AB073614 has recently shown to be aberrantly increased and identified as a poor prognostic biomarker in human glioma. However, the potential mechanisms remain unknown. This study demonstrated that AB073614 expression was significantly upregulated in both glioma tissues and cell lines, and glioma patients with high AB073614 expression had lower overall survival rates. Importantly, silencing AB073614 expression remarkably inhibited U251 cell proliferation, migration, an ...[more]

PMID: 29029454

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Project description:Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.

Dataset Information

Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/?-catenin signaling through downregulating SOX7.

Publications

Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/β-catenin signaling through downregulating SOX7.

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