Glucose transporter 4 promotes head and neck squamous cell carcinoma metastasis through the TRIM24-DDX58 axis.
Glucose transporter 4 promotes head and neck squamous cell carcinoma metastasis through the TRIM24-DDX58 axis.
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葡萄糖转运蛋白4通过TRIM 24-DDX 58轴促进头颈鳞癌转移
DOI：
10.1186/s13045-016-0372-0
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发表时间：
2017-01-07
影响因子：
28.5
通讯作者：
Hsiao M
中科院分区：
文献类型：
--
作者：
Chang YC;Chi LH;Chang WM;Su CY;Lin YF;Chen CL;Chen MH;Chang PM;Wu AT;Hsiao M
头颈部鳞状细胞癌（HNSCC）是一个独特的和主要的健康问题在世界范围内。已经在HNSCC细胞中观察到葡萄糖摄取和有氧糖酵解的显著增加。葡萄糖转运蛋白（GLUT）是糖酵解途径中的主要枢纽，其中GLUT 4具有最高的葡萄糖亲和力。然而，GLUT 4在HNSCC中的作用尚未得到充分认识。在HNSCC队列中进行计算机模拟分析，以确定与HNSCC患者预后相关的最重要的葡萄糖转运蛋白。采用免疫组织化学方法分析90例HNSCC患者的组织芯片，以确定GLUT 4与预后的关系。进行GLUT 4的互补功能表达和敲低研究以研究GLUT 4是否在体外和体内的HNSCC细胞迁移和侵袭中起作用。GLUT 4在诱导HNSCC细胞转移中的作用的详细分子机制被确定。我们的临床病理分析显示，口腔鳞状细胞癌患者中GLUT 4表达增加与总生存率（OS，P = 0.035）和无复发生存率（RFS，P = 0.001）显著相关。此外，在内源性GLUT 4表达低的细胞系中，GLUT 4的异位过表达导致体外和体内迁移能力的显著增加，而在GLUT 4沉默的细胞中观察到相反的表型。利用GLUT 4过表达模型，我们进行了基因表达微阵列和不相容性通路分析（IPA），以确定转录因子TRIM 24是GLUT 4的主要下游调节因子。此外，DDX 58被证实是TRIM 24的下游靶标，其下调对于HNSCC细胞中GLUT 4-TRIM 24活化诱导的迁移表型是必需的。在这里，我们确定了HNSCC进展中葡萄糖代谢的改变，并表明这可能部分归因于GLUT 4和TRIM 24之间的新联系。这一新的信号传导轴可能在将来用于HNSCC的预后和治疗。本文的在线版本（doi：10.1186/s13045-016-0372-0）包含补充材料，可供授权用户使用。
Head and neck squamous cell carcinoma (HNSCC) represents a unique and major health concern worldwide. Significant increases in glucose uptake and aerobic glycolysis have been observed in HNSCC cells. Glucose transporters (GLUTs) represent a major hub in the glycolysis pathway, with GLUT4 having the highest glucose affinity. However, GLUT4’s role in HNSCC has not been fully appreciated. An in silico analysis was performed in HNSCC cohorts to identify the most significant glucose transporter associated with HNSCC patient prognosis. An immunohistochemical analysis of a tissue microarray with samples from 90 HNSCC patients was used to determine the association of GLUT4 with prognosis. Complementary functional expression and knockdown studies of GLUT4 were performed to investigate whether GLUT4 plays a role in HNSCC cell migration and invasion in vitro and in vivo. The detailed molecular mechanism of the function of GLUT4 in inducing HNSCC cell metastasis was determined. Our clinicopathologic analysis showed that increased GLUT4 expression in oral squamous cell carcinoma patients was significantly associated with a poor overall survival (OS, P = 0.035) and recurrence-free survival (RFS, P = 0.001). Furthermore, the ectopic overexpression of GLUT4 in cell lines with low endogenous GLUT4 expression resulted in a significant increase in migratory ability both in vitro and in vivo, whereas the reverse phenotype was observed in GLUT4-silenced cells. Utilizing a GLUT4 overexpression model, we performed gene expression microarray and Ingenuity Pathway Analysis (IPA) to determine that the transcription factor tripartite motif-containing 24 (TRIM24) was the main downstream regulator of GLUT4. In addition, DDX58 was confirmed to be the downstream target of TRIM24, whose downregulation is essential for the migratory phenotype induced by GLUT4–TRIM24 activation in HNSCC cells. Here, we identified altered glucose metabolism in the progression of HNSCC and showed that it could be partially attributed to the novel link between GLUT4 and TRIM24. This novel signaling axis may be used for the prognosis and therapeutic treatment of HNSCC in the future. The online version of this article (doi:10.1186/s13045-016-0372-0) contains supplementary material, which is available to authorized users.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
5.9
作者：
Masin M;Vazquez J;Rossi S;Groeneveld S;Samson N;Schwalie PC;Deplancke B;Frawley LE;Gouttenoire J;Moradpour D;Oliver TG;Meylan E
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3.3
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5.6
作者：
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