Metabolic reprogramming, in which energetic metabolism changes from oxidative phosphorylation to glycolysis, is well-accepted as a hallmark of cancers including hepatocellular carcinoma (HCC). A growing body of evidence suggests the involvement of oncogenes and tumor suppressor genes in the control of metabolic reprogramming. In this study, we attempt to investigate whether loss of PTEN, a recognized tumor suppressor, drives metabolic reprogramming of HCC. Cancerous liver tissues were surgically resected from 128 HCC patients, with 43 adjacent noncancerous liver tissues as control. Aerobic glycolysis (Warburg effect) was reflected by measurements of glucose uptake and lactate production, mitochondrial membrane potential collapse was observed by JC-1 staining, glycolytic rate and mitochondrial respiration were evaluated by determining glycolytic proton efflux rate (glycoPER) and oxygen consumption rate (OCR) in cultured human HHCC cells. Reciprocal expression of PTEN and PI3K was determined in cancer liver tissues. Overexpression of PTEN suppressed the Warburg effect, as evidenced by reductions in glucose uptake and lactate production, maintenance of mitochondrial function, and transformation of energetic metabolism from glycolysis to oxidative phosphorylation in cultured PTEN-negative HHCC cells. Importantly, 740 Y-P, a PI3K agonist that leads to activation of the PI3K pathway, partially abrogated the function of PTEN and reprogramed glucose metabolism in cultured HHCC cells. The discovery that loss of PTEN allows the tumor metabolic program has been a major advance in understanding the carcinogenesis of HCC. Graphic abstract showing that loss of PTEN regulates the tumor metabolic program in hepatocellular carcinoma. Loss of PTEN leads to activation of the PI3K pathway enhances the Warburg effect, thereby promoting the development of hepatocellular carcinoma.

中文翻译：

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PTEN 表达的丧失与肝细胞癌中 PI3K 通路依赖性代谢重编程有关。

代谢重编程，其中能量代谢从氧化磷酸化转变为糖酵解，被广泛接受为包括肝细胞癌 (HCC) 在内的癌症的标志。越来越多的证据表明致癌基因和肿瘤抑制基因参与控制代谢重编程。在这项研究中，我们试图调查 PTEN（一种公认的肿瘤抑制因子）的缺失是否会驱动 HCC 的代谢重编程。从 128 名 HCC 患者中手术切除癌性肝组织，其中 43 个相邻的非癌性肝组织作为对照。有氧糖酵解（Warburg 效应）通过葡萄糖摄取和乳酸产生的测量来反映，通过 JC-1 染色观察到线粒体膜电位崩溃，通过测定培养的人类 HHCC 细胞中的糖酵解质子流出率 (glycoPER) 和耗氧率 (OCR) 来评估糖酵解率和线粒体呼吸。在癌肝组织中确定了 PTEN 和 PI3K 的相互表达。PTEN 的过表达抑制了 Warburg 效应，这可以通过葡萄糖摄取和乳酸产生的减少、线粒体功能的维持以及在培养的 PTEN 阴性 HHCC 细胞中将能量代谢从糖酵解转化为氧化磷酸化来证明。重要的是，740 YP，一种导致 PI3K 通路激活的 PI3K 激动剂，在培养的 HHCC 细胞中部分取消了 PTEN 的功能并重新编程了葡萄糖代谢。PTEN 缺失允许肿瘤代谢程序的发现是了解 HCC 致癌作用的重大进展。图形摘要显示 PTEN 的缺失调节肝细胞癌中的肿瘤代谢程序。PTEN 的缺失导致 PI3K 通路的激活增强了 Warburg 效应，从而促进了肝细胞癌的发展。