Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma
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(2020) 18:97
RESEARCH
Open Access
Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma Chenying Lu1,2†, Shiji Fang1,2†, Qiaoyou Weng1,2†, Xiuling Lv1,2, Miaomiao Meng1,2, Jinyu Zhu1,2, Liyun Zheng1,2, Yumin Hu1,2, Yang Gao1,2, Xulu Wu1,2, Jianting Mao1,2, Bufu Tang1,2, Zhongwei Zhao1,2, Li Huang3* and Jiansong Ji1,2*
Abstract Background: 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. Methods: 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. Results: 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 glycolysisrelated 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. Conclusions: 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. Keywords: Liver cancer, Tumor metabolism, Energy metabolism, SPP1
* Correspondence: [email protected]; [email protected] † Chenying Lu, Shiji Fang and Qiaoyou Weng contributed equally to this work. 3 School of Materials Science and Engineering, Shanghai Key Laboratory of D&A for Metal-Functional Materials, Tongji University, Shanghai 201804, PR China 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, Lishui 323000, PR China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as yo
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