Chang Yu-Chan, Chi Li-Hsing, Chang Wei-Ming, Su Chia-Yi, Lin Yuang-Feng, Chen Chi-Long, Chen Ming-Huang, Chang Peter Mu-Hsin, Wu Alex T H, Hsiao Michael
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
J Hematol Oncol. 2017 Jan 7;10(1):11. doi: 10.1186/s13045-016-0372-0.
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.
头颈部鳞状细胞癌（HNSCC）是全球范围内一个独特且主要的健康问题。在HNSCC细胞中已观察到葡萄糖摄取和有氧糖酵解显著增加。葡萄糖转运蛋白（GLUTs）是糖酵解途径中的一个主要枢纽，其中GLUT4具有最高的葡萄糖亲和力。然而，GLUT4在HNSCC中的作用尚未得到充分认识。
对HNSCC队列进行了计算机分析，以确定与HNSCC患者预后相关的最显著的葡萄糖转运蛋白。使用来自90例HNSCC患者样本的组织微阵列进行免疫组织化学分析，以确定GLUT4与预后的关联。进行了GLUT4的互补功能表达和敲低研究，以调查GLUT4在体外和体内HNSCC细胞迁移和侵袭中是否发挥作用。确定了GLUT4诱导HNSCC细胞转移功能的详细分子机制。
我们的临床病理分析表明，口腔鳞状细胞癌患者中GLUT4表达增加与总体生存率（OS，P = 0.035）和无复发生存率（RFS，P = 0.001）显著相关。此外，在低内源性GLUT4表达的细胞系中异位过表达GLUT4导致体外和体内迁移能力显著增加，而在GLUT4沉默的细胞中观察到相反的表型。利用GLUT4过表达模型，我们进行了基因表达微阵列和 Ingenuity 通路分析（IPA），以确定转录因子含三联基序蛋白24（TRIM24）是GLUT4的主要下游调节因子。此外，DDX58被证实是TRIM24的下游靶点，其下调对于GLUT4-TRIM24激活诱导的HNSCC细胞迁移表型至关重要。
在此，我们确定了HNSCC进展过程中葡萄糖代谢的改变，并表明这可能部分归因于GLUT4与TRIM24之间的新联系。这个新的信号轴未来可能用于HNSCC的预后评估和治疗。
