FBW7 (F-box andWDRepeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer
FBW7 (F-box andWDRepeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer
复制标题
FBW7（含 F-box 和 WDR 重复结构域 7）通过靶向胰腺癌中的 c-Myc/TXNIP（硫氧还蛋白结合蛋白）轴负向调节葡萄糖代谢
DOI：
10.1158/1078-0432.ccr-15-2380
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发表时间：
2016-08-01
影响因子：
11.5
通讯作者：
Yu, Xianjun
中科院分区：
文献类型：
--
作者：
Ji, Shunrong;Qin, Yi;Yu, Xianjun
目的：FBW 7通过靶向破坏癌蛋白而发挥肿瘤抑制作用。我们先前报道了KRAS的致癌突变通过Ras-Raf-MEK-ERK通路抑制肿瘤抑制因子FBW 7，该通路促进胰腺癌细胞的增殖和存活。然而，FBW 7抑制胰腺癌的潜在机制仍未被探索。在这里，我们试图阐明FBW 7在胰腺癌糖代谢和malignancy.Experimental设计的功能：结合最大标准化摄取值（SUVmax），这是通过术前PET/CT扫描，免疫组化染色，我们分析了SUVmax和FBW 7在胰腺癌组织中的表达之间的相关性。FBW 7对葡萄糖代谢的影响在体外和体内得到进一步验证。结果：胰腺癌患者中FBW 7的表达水平与SUVmax呈负相关。FBW 7在体外显著抑制胰腺癌细胞的葡萄糖代谢。使用异种移植模型，MicroPET/CT成像结果表明FBW 7显著降低异种移植肿瘤中的18F-氟脱氧葡萄糖（18F-FDG）摄取。基因表达谱数据显示，TXNIP，代谢转化的负调控因子，是FBW 7的下游靶点。从机制上讲，我们证明了TXNIP是一个c-Myc的靶基因，FBW 7调节TXNIP的表达在c-Myc依赖的marty.Conclusions：因此，我们的研究结果表明，FBW 7作为葡萄糖代谢的负调节通过调节c-Myc/TXNIP轴在胰腺癌。(C)2016年AACR。
Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.Experimental Design: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways.Results: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner.Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. (C) 2016 AACR.