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首页> 外文期刊>Cell biology international. >TNF‐α mediated MEK–ERK signaling in invasion with putative network involving NF‐κB and STAT‐6: a new perspective in glioma
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TNF‐α mediated MEK–ERK signaling in invasion with putative network involving NF‐κB and STAT‐6: a new perspective in glioma

机译：TNF-α介导的MEK-ERK信号在侵袭网络中涉及NF-κB和Stat-6：胶质瘤的新透视

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Abstract Glioblastoma is the most common malignant primary brain tumor with poor prognosis. Invasion involves pro‐inflammatory cytokines and major signaling hubs. Tumor necrosis factor‐α (TNF‐α) acts as a master switch in establishing an intricate link between inflammation and cancer. The present study attempted to explore the possible implication of MAPK extracellular signaling‐regulated kinase kinase (MEK)–extracellular signaling‐regulated kinase (ERK) signaling pathway and expression of nuclear factor‐κB (NF‐κB), signal transducers and activators of transcription‐6 (STAT‐6), ERK, and phosphorylated‐ERK (p‐ERK) signaling proteins in TNF‐α microenvironment. U0126 and PD98059 were used to inhibit the MEK–ERK1/2 pathway. TNF‐α stimulation enhanced invasion in U87MG, U251MG and patient‐derived primary glioma cells, whereas cell viability was not altered. Matrix metalloproteinase‐2 (MMP‐2) activity was increased only in U251MG glioma cells. These data suggest that TNF‐α microenvironment plays an important role in the invasion of U251MG, U87MG, and patient‐derived primary glioma cells, without any cytotoxic effect. The MMP‐2 activity is differentially regulated by TNF‐α stimulation in these cells. TNF‐α stimulation upregulated the protein expression of ERK‐1, ERK‐2 and also increased the level of p‐ERK1/2. TNF‐α stimulation further upregulated the expression of NF‐κB1, STAT‐6 in tandem with Ras–MEK signaling system in U87MG cells, which emphasized the possible involvement of these signaling hubs in the glioma microenvironment. MEK–ERK inhibitors significantly attenuated the invasion of U87MG cells mediated by the TNF‐α stimulation, probably through their inhibitory impact on p‐ERK1/2 and ERK‐2. This study provides the possible rationale of invasion by glioma cells in a TNF‐α‐induced pro‐inflammatory milieu, which involves direct role of MEK–ERK signaling, with possible implication of NF‐κB and STAT‐6.
机译：摘要胶质母细胞瘤是最常见的恶性原发性脑肿瘤，预后差。侵袭涉及促炎细胞因子和主要信号枢纽。肿瘤坏死因子-α（TNF-α）用作建立炎症和癌症之间复杂联系的主开关。目前的研究试图探讨MAPK细胞外信号调节激酶激酶激酶（MEK） - X细胞信号调节激酶（ERK）信号传导途径和核因子-κB（NF-κB），信号传感器和转录激活剂的表达的可能暗示TNF-α微环境中的-6（STAT-6），ERK和磷酸化-ERK（P-ERK）信号蛋白。 U0126和PD98059用于抑制MEK-ERK1 / 2途径。 TNF-α刺激增强U87MG，U251MG和患者衍生的原发性胶质瘤细胞的侵袭，而细胞活力没有改变。基质金属蛋白酶-2（MMP-2）仅在U251MG胶质瘤细胞中增加。这些数据表明，TNF-α微环境在没有任何细胞毒性效应的情况下在侵袭U251MG，U87MG和患者衍生的原发性胶质瘤细胞中起重要作用。 MMP-2活性通过这些细胞中的TNF-α刺激差异调节。 TNF-α刺激上调了ERK-1，ERK-2的蛋白质表达，也增加了P-ERK1 / 2的水平。 TNF-α刺激进一步上调了U87MG细胞中RAS-MEK信号系统串联NF-κB1，Stat-6的表达，这强调了这些信号传导枢纽在胶质瘤微环境中的可能参与。 Mek-ERK抑制剂显着减弱了由TNF-α刺激介导的U87mg细胞的侵袭，可能是通过对P-ERK1 / 2和ERK-2的抑制作用。本研究提供了TNF-α-诱导的促炎Milieu中的胶质瘤细胞侵袭的可能理由，这涉及MEK-ERK信号传导的直接作用，具有NF-κB和Stat-6的可能含义。

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