Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

Cell Communication and Signaling

Zhongwei Zhao¹  Shiji Fang¹  Yumin Hu¹  Xiuling Lv¹  Miaomiao Meng¹  Jianting Mao¹  Xulu Wu¹  Jiansong Ji¹  Yang Gao¹  Qiaoyou Weng¹  Bufu Tang¹  Jinyu Zhu¹  Liyun Zheng¹  Chenying Lu¹  Li Huang² 

[1] Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University /Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, 323000, Lishui, PR China;Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University /Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, 323000, Lishui, PR China;School of Materials Science and Engineering, Shanghai Key Laboratory of D&A for Metal-Functional Materials, Tongji University, 201804, Shanghai, PR China;

关键词: Liver cancer;    Tumor metabolism;    Energy metabolism;    SPP1;   

DOI  :  10.1186/s12964-020-00539-4

来源: Springer

【 摘 要 】

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 Abstract

【 授权许可】

CC BY