LRRC4 inhibits glioblastoma cell proliferation, migration, and angiogenesis by downregulating pleiotropic cytokine expression and responses
LRRC4 inhibits glioblastoma cell proliferation, migration, and angiogenesis by downregulating pleiotropic cytokine expression and responses
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LRRC4 通过下调多效细胞因子表达和反应来抑制胶质母细胞瘤细胞增殖、迁移和血管生成
DOI：
10.1002/jcp.21163
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发表时间：
2008-01-01
影响因子：
5.6
通讯作者：
Li, Guiyuan
中科院分区：
文献类型：
--
作者：
Wu, Minghua;Huang, Chen;Li, Guiyuan
富含亮氨酸的重复C4 （LRRC4）已被证明可以抑制胶质瘤细胞的增殖，然而，对LRRC4作用的机制知之甚少。在这里，我们展示了两个稳定表达LRRC4的胶质母细胞瘤U251细胞克隆的建立。LRRC4的表达可显著抑制胶质瘤细胞中某些细胞因子及其受体的表达，并可显著降低细胞因子诱导的AP-1、NF-kB和CyclinD1的活化。此外，LRRC4在胶质瘤细胞中的表达显著下调自发和细胞因子诱导的K-RAS表达以及c-Raf、ERK、AKT、NF-kBp65、p70S6K和PKC的磷酸化，表明LRRC4抑制受体酪氨酸激酶（RTK）信号通路。此外，使用bFGF、igf1或IGF2刺激LRRC4(-/-)，但不刺激LRRC4(+)，胶质瘤细胞增殖，表明LRRC4减轻了细胞因子刺激的胶质瘤细胞增殖。此外，用EGF、IGF2或PDGF处理LRRC4（-/-）胶质瘤细胞可以促进长距离动员，但对LRRC4（+）胶质瘤细胞的迁移几乎没有诱导作用，这表明LRRC4延缓了细胞因子促进的胶质瘤细胞在体外的迁移。最后，经VEGF处理的人血管内皮细胞（ECV304）在体外生长、排列并形成空心管状结构。相比之下，经VEGF处理的LRRC4(+) ECV304不能形成血管-管结构。综上所述，LRRC4的表达抑制了某些生长因子、细胞因子及其受体的表达，抑制了胶质瘤细胞对细胞因子刺激的响应能力，从而抑制了胶质瘤细胞的增殖。可以想象，诱导LRRC4表达可能为临床治疗人类胶质瘤提供新的干预手段。
Leucine-rich repeat C4 (LRRC4) has been shown to inhibit glioma cell proliferation, however, little is known about the mechanism(s) underlying the action of LRRC4. Here, we show that two glioblstoma U251 cell clones stably expressing LRRC4 were established. LRRC4 expression significantly inhibited the expression of some cytokines and their receptors determined by microarray and Western blot assays, and dramatically reduced cytokine-induced AP-1, NF-kB, and CyclinD1 activation in glioma cells. Furthermore, LRRC4 expression in glioma cells significantly downregulated spontaneous and cytokine-induced expression of K-RAS and phosphorylation of c-Raf, ERK, AKT, NF-kBp65, p70S6K, and PKC, suggesting that LRRC4 inhibited receptor tyrosine kinase (RTK) signaling pathways. Moreover, treatment with bFGF, IGF 1, or IGF2 stimulated LRRC4(-/-), but not the LRRC4(+), glioma cell proliferation, indicating that LRRC4 mitigated cytokine-stimulated proliferation in glioma cells. In addition, treatment of LRRC4(-/-) glioma cells with EGF, IGF2, or PDGF promoted long distance mobilization, but induced little migration in LRRC4(+) glioma cells, suggesting that LRRC4 retarded cytokine-promoted glioma cell migration in vitro. Finally, human vessel endothelial cells (ECV304) treated with VEGF grew, aligned and formed hollow tube-like structures in vitro. In contrast, LRRC4(+) ECV304 treated with VEGF failed to form vessel-tube structures. Collectively, LRRC4 expression inhibited the expression of some growth factors, cytokines and their receptors, and the capacity of glioma cells responding to cytokine stimulation, leading to inhibition of glioma cell proliferation. Conceivably, induction of LRRC4 expression may provide new intervention for human glioma in the clinic.