GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis
GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis
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GBP3通过SQSTM1/p62-ERK1/2轴促进神经胶质瘤细胞增殖
DOI：
10.1016/j.bbrc.2017.11.050
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发表时间：
2018-01-01
影响因子：
3.1
通讯作者：
Lan, Qing
中科院分区：
文献类型：
--
作者：
Xu, Hui;Sun, Lili;Lan, Qing
鸟苷酸结合蛋白（GBP）是干扰素诱导的大G蛋白酶，在细胞自主免疫中起着至关重要的作用。然而，GBP在癌症中的生物学功能仍然难以捉摸。GBP 3在成人脑中特异性表达。在这里，我们表明GBP 3在人类神经胶质瘤肿瘤和神经胶质瘤细胞系中高度升高。过表达GBP 3显著增加胶质瘤细胞增殖，而通过RNA干扰沉默GBP 3产生相反的效果。我们进一步表明，GBP 3的表达能够诱导隔离体-1（SQSTM 1，也称为p62）的表达和激活细胞外信号调节激酶（ERK 1/2）。SQSTM 1-ERK 1/2信号级联对于GBP 3促进的细胞生长是必不可少的，因为SQSTM 1的耗尽显著降低磷酸化ERK 1/2水平和GBP 3介导的细胞生长，并且丝裂原活化蛋白激酶/ERK激酶的抑制消除了GBP 3诱导的胶质瘤细胞增殖。因此，GBP 3过表达可显著促进胶质瘤的生长，其表达与胶质瘤患者的生存率呈负相关。总而言之，这些结果首次表明GBP 3通过调节SQSTM 1-ERK 1/2途径促进胶质瘤细胞的增殖，GBP 3可能成为抗胶质瘤的新的潜在治疗靶点。(C)2017爱思唯尔公司All rights reserved.
Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma. (C) 2017 Elsevier Inc. All rights reserved.