Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

Chenying Lu,Miaomiao Meng,Yang Gao,Li Huang,Jianting Mao,Yumin Hu,Xiuling Lv,Qiaoyou Weng,Zhongwei Zhao,Liyun Zheng,Jiansong Ji,Jinyu Zhu,Shiji Fang,Bufu Tang,Xulu Wu

doi:10.1186/s12964-020-00539-4

Abstract

BackgroundCancer 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.MethodsMolecular 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.ResultsIncreased 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.ConclusionsOur 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.C2sFgipyoX_pHMB_P3qafcVideo

Highlights

Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect
Many risk factors contributes for Hepatocellular carcinoma (HCC) initiation, such as infection with either hepatitis B virus or hepatitis C virus, nonalcoholic steatohepatitis, alcoholic cirrhosis, and exposure to environmental toxins [2, 3]
Glycolysis-derived lactate can lead to an acidic tumor microenvironment, which is profoundly implicated in tumor progression by modulating tumor metastasis and immune response [10]

Summary

Introduction

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. Uncovering the mechanisms underlying HCC progression to improve clinical outcomes and to develop better therapeutic strategies is of paramount importance [5]. Different from most normal cells, cancer cells metabolize glucose to lactate even in the presence of sufficient oxygen, a phenomenon termed aerobic glycolysis, known as “Warburg effect” [8]. The aerobic glycolysis is characterized by a much higher rate of glucose uptake, consumption and lactate release in cancer cells. Increased glycolysis facilitates cancer cells to rapid utilization of glucose to produce abundant ATP. The molecular mechanism for the Warburg effect in HCC is far from explored

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