Shang Runze, Pu Meng, Li Yu, Wang Desheng
Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Oncol Rep. 2017 Apr;37(4):2261-2269. doi: 10.3892/or.2017.5472. Epub 2017 Feb 22.
The Forkhead box M1 (FOXM1) transcription factor plays crucial roles in the initiation and progression of various malignancies, including hepatocellular carcinoma (HCC). However, the mechanism by which FOXM1 regulates cancer metabolism remains unclear. In the present study, overexpression and RNA interference (RNAi) approaches were used to investigate the role of FOXM1 in the regulation of glycolysis in vitro. Luciferase reporter assays were used to explore the transcriptional regulation of the glucose transporter 1 (GLUT1) promoter by FOXM1. Then, immunohistochemical staining was used to examine the expression of FOXM1 and GLUT1 in 100 paired HCC and adjacent non-cancerous liver tissues. Chi-square test and logistic regression analysis were performed to evaluate the association between FOXM1 and GLUT1 expression with clinicopathological characteristics. Our data showed that FOXM1 promoted glycolysis in the HCC cells. FOXM1 knockdown significantly reduced the expression of GLUT1 among key glycolysis-related molecules in the different HCC cell lines. Glucose uptake and lactate production assay showed that FOXM1 positively regulated glycolysis based on GLUT1 expression. Moreover, FOXM1 overexpression increased and knockdown decreased GLUT1 expression. Luciferase reporter assays showed that the -206 to -199 bp region of the GLUT1 promoter is important for FOXM1 to enhance GLUT1 promoter activity. The results of the IHC analysis showed that the protein expression of FOXM1 and GLUT1 was closely related to the tumor histological grade and TNM stage. In addition, GLUT1 expression was also related to microvascular invasion. In conclusion, overexpression of FOXM1 and GLUT1 may play critical roles in HCC. FOXM1 promotes HCC glycolysis by transactivating GLUT1 expression.
叉头框M1（FOXM1）转录因子在包括肝细胞癌（HCC）在内的多种恶性肿瘤的发生和发展中起着关键作用。然而，FOXM1调节癌症代谢的机制仍不清楚。在本研究中，采用过表达和RNA干扰（RNAi）方法在体外研究FOXM1在糖酵解调节中的作用。利用荧光素酶报告基因检测来探索FOXM1对葡萄糖转运蛋白1（GLUT1）启动子的转录调控。然后，采用免疫组织化学染色检测100对HCC及癌旁非癌肝组织中FOXM1和GLUT1的表达。进行卡方检验和逻辑回归分析以评估FOXM1和GLUT1表达与临床病理特征之间的关联。我们的数据表明，FOXM1促进HCC细胞中的糖酵解。在不同的HCC细胞系中，敲低FOXM1可显著降低关键糖酵解相关分子中GLUT1的表达。葡萄糖摄取和乳酸生成检测表明，FOXM1基于GLUT1的表达对糖酵解起正向调节作用。此外，FOXM1过表达增加而敲低则降低GLUT1的表达。荧光素酶报告基因检测表明，GLUT1启动子的-206至-199 bp区域对于FOXM1增强GLUT1启动子活性很重要。免疫组织化学分析结果表明，FOXM1和GLUT1的蛋白表达与肿瘤组织学分级和TNM分期密切相关。此外，GLUT1表达也与微血管侵犯有关。总之，FOXM1和GLUT1的过表达可能在HCC中起关键作用。FOXM1通过反式激活GLUT1表达促进HCC糖酵解。
