Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients. Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models. Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvβ3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvβ3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN. Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC.

中文翻译：

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综合分析揭示了肝细胞癌中关键的糖酵解调节因子。

癌细胞主要利用有氧糖酵解来产生能量，这种现象被称为 Warburg 效应。增加的有氧糖酵解支持癌细胞存活和快速增殖，并预测癌症患者的不良预后。来自癌症基因组图谱 (TCGA) 队列的分子图谱用于分析糖酵解基因特征在人类癌症中的预后价值。对与肝细胞癌 (HCC) 糖酵解有关的关键驱动因素进行了功能获得和功能丧失研究。通过实时 qPCR、蛋白质印迹、免疫组织化学、荧光素酶报告基因测定以及异种移植和二乙基亚硝胺 (DEN) 诱导的 HCC 小鼠模型研究了骨桥蛋白 (OPN) 介导的糖酵解的分子机制。糖酵解增加预示着多种人类癌症的不良临床结果，尤其是肝癌。然后，我们确定了一些与 HCC 糖酵解相关的差异表达基因。功能获得和功能丧失研究表明 OPN 促进，而 SPP2、LECT2、SLC10A1、CYP3A4、HSD17B13 和 IYD 抑制 HCC 细胞糖酵解，如葡萄糖利用、乳酸产生和细胞外酸化率所揭示。这些糖酵解相关基因对 HCC 细胞表现出显着的促肿瘤或抑癌作用，并且这些作用是糖酵解依赖性的。从机制上讲，OPN 通过激活 αvβ3-NF-κB 信号传导增强 HCC 糖酵解。OPN-αvβ3 轴的遗传或药理学阻断抑制异种移植肿瘤模型中的 HCC 糖酵解和 DEN 诱导的肝癌发生。