Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Oncogene. 2018 Feb 8;37(6):744-755. doi: 10.1038/onc.2017.363. Epub 2017 Oct 23.
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 β4 (ITGB4) and activated ITGB4/focal adhesion kinase (FAK)/glycogen synthase kinase 3β 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 α (HIF-1α) promoter activity to regulate glucose metabolism. The micro-positron emission tomography/computed tomography imaging of xenograft model showed that ECM1 substantially increased F-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-1α signal pathway and have important implications for the development of therapeutic target to prevent tumor metastasis and recurrence.
细胞外基质蛋白 1（ECM1）与多种恶性肿瘤的强侵袭性和不良预后相关，但潜在机制尚不清楚。本研究旨在阐明 ECM1 在胃癌（GC）细胞转移和葡萄糖代谢中的作用。GC 患者血清和组织中 ECM1 的水平与肿瘤侵袭和复发呈正相关。ECM1 表达的遗传操作影响 GC 细胞系的细胞转移和葡萄糖代谢。增强的 ECM1 表达促进与上皮-间充质转化（EMT）和葡萄糖代谢相关的基因表达水平。有趣的是，我们的结果表明 ECM1 可直接与整合素 β4（ITGB4）相互作用，并激活 ITGB4/黏着斑激酶（FAK）/糖原合酶激酶 3β 信号通路，从而进一步诱导转录因子 SOX2 的表达。SOX2 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，SOX2 增强缺氧诱导因子α（HIF-1α）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，ECM1 可显著增加异种移植瘤中 F-氟脱氧葡萄糖的摄取。通过体内小鼠尾静脉注射实验，也发现 ECM1 可增加肺表面转移。这些发现为 ECM1 通过诱导 ITGB4/FAK/SOX2/HIF-1α 信号通路调节 GC 细胞转移和葡萄糖代谢提供了证据，并对开发预防肿瘤转移和复发的治疗靶点具有重要意义。
