Abstract
BackgroundMetabolic 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.MethodsCancerous 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.ResultsReciprocal 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.ConclusionsThe discovery that loss of PTEN allows the tumor metabolic program has been a major advance in understanding the carcinogenesis of HCC.Bo7HehjAYW3ADh-U-ymoVNVideo abstractGraphical abstractGraphic 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.
Highlights
Metabolic reprogramming, in which energetic metabolism changes from oxidative phosphorylation to glycolysis, is well-accepted as a hallmark of cancers including hepatocellular carcinoma (HCC)
Human specimens Cancerous liver tissues were surgically resected from 128 HCC patients who had been diagnosed with HCC at Qilu Hospital of Shandong University from July 2011 to July 2014, with 43 adjacent noncancerous liver tissues as controls
To investigate oncogenic and prognostic performance of Phosphatase and tensin homolog (PTEN) and its underlying mechanism in HCC, we first performed immunohistochemical staining to examine the expression of PTEN and PI3K in 128 cancerous liver tissues and 43 adjacent noncancerous liver tissues
Summary
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. We attempt to investigate whether loss of PTEN, a recognized tumor suppressor, drives metabolic reprogramming of HCC. Hepatocellular carcinoma (HCC) represents a malignant tumor predominantly arising in the setting of cirrhosis, causing an estimated one million deaths on a global scale in 2030 [1]. An enhanced understanding of the mechanism underlying HCC pathogenesis, recurrence and metastasis is required to achieve early diagnosis and to further develop more effective treatment modalities. Metabolic reprogramming is an emerging hallmark in liver cancer
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