PDF(Pubmed)
Abstract：
Monosomy 3 in uveal melanoma (UM) increases the risk of lethal metastases, mainly in the liver, which serves as the major site for the storage of excessive glucose and the metabolization of the dietary flavonoid quercetin. Although primary UMs with monosomy 3 exhibit a higher potential for basal glucose uptake, it remains unknown as to whether glycolytic capacity is altered in such tumors. Herein, we initially analyzed the expression of n = 151 genes involved in glycolysis and its interconnected branch, the \"pentose phosphate pathway (PPP)\", in the UM cohort of The Cancer Genome Atlas Study and validated the differentially expressed genes in two independent cohorts. We also evaluated the effects of quercetin on the growth, survival, and glucose metabolism of the UM cell line 92.1. The rate-limiting glycolytic enzyme PFKP was overexpressed whereas the ZBTB20 gene (locus: 3q13.31) was downregulated in the patients with metastases in all cohorts. Quercetin was able to impair proliferation, viability, glucose uptake, glycolysis, ATP synthesis, and PPP rate-limiting enzyme activity while increasing oxidative stress. UMs with monosomy 3 display a stronger potential to utilize glucose for the generation of energy and biomass. Quercetin can prevent the growth of UM cells by interfering with glucose metabolism.
摘要：
葡萄膜黑色素瘤（UM）中的单体性3增加了致命转移的风险，主要在肝脏，它是储存过量葡萄糖和膳食类黄酮槲皮素代谢的主要场所。尽管具有3型一元性的原发性UMs表现出更高的基础葡萄糖摄取潜力，这类肿瘤的糖酵解能力是否发生改变仍是未知的。在这里，我们最初分析了参与糖酵解的n=151个基因及其相互联系的分支的表达，“磷酸戊糖途径(PPP)”，在癌症基因组图谱研究的UM队列中，并在两个独立的队列中验证了差异表达基因。我们还评估了槲皮素对生长的影响，生存,和UM细胞系92.1的葡萄糖代谢。在所有队列中有转移的患者中，限速糖酵解酶PFKP过表达，而ZBTB20基因（基因座：3q13.31）下调。槲皮素能抑制增殖,生存能力，葡萄糖摄取，糖酵解,ATP合成，和PPP限速酶活性，同时增加氧化应激。具有一元性3的UMs显示出更强的利用葡萄糖产生能量和生物质的潜力。槲皮素可以通过干扰葡萄糖代谢来阻止UM细胞的生长。
