title: CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway.
abstract: OBJECTIVE
  Cancer cells exhibit the reprogrammed metabolism characterized by high level of glycolysis even in the presence of oxygen. Aerobic glycolysis, known as the Warburg effect, supplies cancer cells with the substrates required for biomass generation. To date, several intracellular signaling mediators have been identified in metabolic regulation of cancer cells. However, it remains largely ambiguous how molecules on the cell surface are involved in regulation of cancer metabolism.
  
  
  METHODS
  In the current study, we established several HCC cell lines differing in their CD147 (a typical transmembrane glycoprotein) expression status by zinc-finger nuclease and RNAi techniques. Then, we systematically investigated the role of CD147 in the regulation of the Warburg effect in HCC cells and explored the underlying mechanism.
  
  
  RESULTS
  We found that CD147 significantly contributed to the reprogramming of glucose metabolism in HCC cells through a p53-dependent way. CD147 facilitated the cell surface expression of MCT1 and lactate export, which led to activation of the PI3K/Akt/MDM2 pathway and thus increased p53 degradation. The gain/loss-of-function studies demonstrated that while CD147 promoted glycolysis, mediated by p53-dependent upregulation of GLUT1 and activation of PFKL, it inhibited mitochondrial biogenesis and functions, mediated by p53-dependent downregulation of PGC1α, TFAM, and p53R2. Additionally, proliferation of HCC cells was suppressed by blocking CD147 and/or MCT1, which resulted in down-regulation of glucose metabolism.
  
  
  CONCLUSIONS
  We demonstrate that CD147 is a crucial regulator of glucose metabolism.
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xingjl@fmmu.edu.cn.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Ke
authors.affiliation: Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yukui
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: jiangjl@fmmu.edu.cn.
authors.forename: Jianli
authors.initials: J
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: zhinanchen@fmmu.edu.cn.
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000332:Aerobiosis; D051926:Basigin / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051272:Glucose Transporter Type 1; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; D051926:Basigin; D005947:Glucose
keywords: EMMPRIN; Glycolysis; Hepatocellular carcinoma; Mitochondrion; Tumor growth