Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer
Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer
复制标题
细胞外基质蛋白1通过诱导整合素β4/FAK/SOX2/HIF-1α信号通路促进胃癌细胞转移和糖代谢
DOI：
10.1038/onc.2017.363
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发表时间：
2018-02-08
期刊：
影响因子：
8
通讯作者：
Wang, Z.
中科院分区：
文献类型：
--
作者：
Gan, L.;Meng, J.;Wang, Z.
细胞外基质蛋白1（ECM 1）与恶性肿瘤的侵袭性强、预后差有关，但其机制尚不清楚。本研究旨在探讨ECM 1在胃癌细胞转移和糖代谢中的作用。胃癌患者血清和组织中ECM 1水平与肿瘤浸润和复发呈正相关。ECM 1表达的遗传操作影响GC细胞系中的细胞转移和糖代谢。增强的ECM 1表达促进与上皮-间质转化（EMT）和葡萄糖代谢相关的基因表达水平。有趣的是，我们的研究结果表明，ECM 1直接与整合素β 4（ITGB 4）相互作用，激活ITGB 4/黏着斑激酶（FAK）/糖原合成酶激酶3 β信号通路，进一步诱导转录因子SOX 2的表达。SOX 2的异常表达改变了EMT因子和葡萄糖代谢酶的基因表达。此外，SOX 2增强缺氧诱导因子α（HIF-1 α）启动子活性，以调节葡萄糖代谢。异种移植模型的微正电子发射断层扫描/计算机断层扫描成像显示，ECM 1显著增加异种移植肿瘤中的F-18-氟脱氧葡萄糖摄取。使用体内小鼠尾静脉注射实验，还发现ECM 1增加肺表面转移。这些发现为ECM 1通过诱导ITGB 4/FAK/SOX 2/HIF-1 α信号通路调节GC细胞转移和糖代谢提供了证据，对开发预防肿瘤转移和复发的治疗靶点具有重要意义。
Extracellular matrix protein 1 (ECM1) is related to strong invasiveness and poor prognosis in major malignancies, but the underlying mechanism remains unknown. Here we aimed to elucidate the function of ECM1 on cell metastasis and glucose metabolism in gastric cancer (GC). The level of ECM1 in sera and tissues of patient with GC were positively correlated with tumor invasion and recurrence. Genetic manipulation of ECM1 expression affected cell metastasis and glucose metabolism in GC cell lines. Enhanced ECM1 expression facilitated gene expression levels associated with epithelial-mesenchymal transition (EMT) and glucose metabolism. Interestingly, our results indicated that ECM1 directly interacted with integrin beta 4 (ITGB4) and activated ITGB4/focal adhesion kinase (FAK)/glycogen synthase kinase 3 beta signaling pathway, which further induced the expression of transcription factor SOX2. Aberrant expression of SOX2 altered gene expression of EMT factors and glucose metabolism enzymes. Furthermore, SOX2 enhanced hypoxia-inducible factor alpha (HIF-1 alpha) promoter activity to regulate glucose metabolism. The micro-positron emission tomography/computed tomography imaging of xenograft model showed that ECM1 substantially increased F-18-fluorodeoxyglucose uptake in xenograft tumors. Using in vivo mouse tail vein injection experiments, ECM1 was also found to increase in lung surface metastasis. These findings provide evidence that ECM1 regulates GC cell metastasis and glucose metabolism by inducing ITGB4/FAK/SOX2/HIF-1 alpha signal pathway and have important implications for the development of therapeutic target to prevent tumor metastasis and recurrence.