Zhang Dainan, Wang Xiaoyin, Wang Xi, Wang Zemin, Ma Shunchang, Zhang Chuanbao, Li Shaomin, Jia Wang
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
J Cancer. 2021 Oct 28;12(24):7277-7286. doi: 10.7150/jca.60049. eCollection 2021.
Even with decades of intensive study, the signaling regulative network of the progression of Glioblastoma (GBM) remains unclear, a deeper understanding of the molecular crosstalk with pathways in GBM is needed to identify new potential targets for treatment. Copine-3 (CPNE3) was a member of a Ga2+ -dependent phospholipid-binding protein and was reported to play a role in multiple cancers. To investigate the expression of CPNE3 in GBM, we applied bioinformatic analysis and clinical samples validation. Then the functional validation of carried out in commercially available glioma cell lines and nude mice model. Also, the GSEA analysis was used to identify the relevant pathways. The role of activated pathway was further validated by pharmacology method. We found that CPNE3 was significantly up-regulated in GBM when compared with adjacent normal tissues, and the overexpression of CPNE3 promoted cell proliferation and inhibiting cell apoptosis and . Also, the principal protein markers of PI3K/AKT pathway were found to be phosphorylated by CPNE3 over-expression, and pathway inhibitor, LY294002, alleviated the cell proliferation enhancement induced by CPNE3 over-expression. Our results showed that the expression of CPNE3 promotes cell proliferation by inhibiting cell apoptosis via activating PI3K/AKT pathway. Thereby enhancing the progression of GBM, which suggest that CPNE3 may play as a tumorigenesis gene may become a promising potential therapeutic target for human GBMs.
即使经过数十年的深入研究，胶质母细胞瘤（GBM）进展的信号调节网络仍不清楚，需要更深入地了解GBM中与各通路的分子串扰，以确定新的潜在治疗靶点。Copine-3（CPNE3）是一种依赖Ca2+的磷脂结合蛋白成员，据报道在多种癌症中发挥作用。为了研究CPNE3在GBM中的表达，我们进行了生物信息学分析和临床样本验证。然后在市售的胶质瘤细胞系和裸鼠模型中进行功能验证。此外，使用基因集富集分析（GSEA）来识别相关通路。通过药理学方法进一步验证激活通路的作用。我们发现，与相邻正常组织相比，CPNE3在GBM中显著上调，CPNE3的过表达促进细胞增殖并抑制细胞凋亡。此外，发现PI3K/AKT通路的主要蛋白标志物被CPNE3过表达磷酸化，并且通路抑制剂LY294002减轻了CPNE3过表达诱导的细胞增殖增强。我们的结果表明，CPNE3的表达通过激活PI3K/AKT通路抑制细胞凋亡来促进细胞增殖。从而促进GBM的进展，这表明CPNE3可能作为一种肿瘤发生基因，可能成为人类GBM有前景的潜在治疗靶点。
