title: Upregulation of CD147 protects hepatocellular carcinoma cell from apoptosis through glycolytic switch via HIF-1 and MCT-4 under hypoxia.
abstract: OBJECTIVE
  Hypoxia is a vital factor in supporting and directing hepatocellular carcinoma (HCC) progression. HIF-1 transactivates target genes involved in metabolic reprogramming and antiapoptosis under hypoxia. However, key molecules involved in HCC hypoxia adaptation remain to be characterized. The aim of this study was to investigate the mechanism and biological function of CD147 on HCC cells resistant to apoptosis under hypoxic conditions.
  
  
  METHODS
  Apoptotic rates of hypoxia-treated HCC cells were investigated by flow cytometer, and the expression levels of CD147, HIF-1α, MCT-1 and MCT-4 were assayed by immune blot. The in vitro glycolytic capacity was investigated in SMMC-7721 cells and 7721-shCD147 cells (CD147 is stably knocked down). Immunohistochemical staining of CD147, Glut-1, MCT-1, MCT-4, LAT-1 and CD98 was detected in tumor tissues from a xenograft model. Immunofluorescence double-labeled staining allowed further exploration of the expression levels and localizations of CD147, MCT-1 and MCT-4.
  
  
  RESULTS
  Upregulation of CD147 under hypoxia correlates with higher viability of HCC cells compared with that in HSC cells. Silencing of CD147 significantly inhibited the glycolytic rate and induced apoptosis in SMMC-7721 cells. The expression level of lactate secretion transporter MCT-1/MCT-4 is dependent on CD147, while the expression level of Glut-1, LAT-1 and CD98 remained unchanged. Particularly, MCT-4 is demonstrated to be essential for the membranal localization of CD147.
  
  
  CONCLUSIONS
  With the above findings, we conclude that within the HCC hypoxic microenvironment, upregulation of CD147 and MCT-4 involved in glycolytic reprogramming is decisively important for the viability of HCC cells under hypoxia adaptation.
authors.affiliation: Institute of Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, People's Republic of China. kexia@zjut.edu.cn.|State Key Laboratory of Cancer Biology, Cell Engineering Research Centre & Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China. kexia@zjut.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Centre & Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Centre & Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Centre & Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Centre & Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China. znchen@fmmu.edu.cn.
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Chen
keywords: Apoptosis; CD147; Hepatocellular carcinoma; Hypoxia; MCT