Xia Ke1,2, Yanke Chen3, Pei Wang3, Jinliang Xing3, Zhinan Chen4. 1. Institute of Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, People's Republic of China. kexia@zjut.edu.cn. 2. 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. 3. 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. 4. 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.
Abstract
PURPOSE: 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.
PURPOSE: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: Renaud Le Floch; Johanna Chiche; Ibtissam Marchiq; Tanesha Naiken; Tanesha Naïken; Karine Ilc; Karine Ilk; Clare M Murray; Susan E Critchlow; Danièle Roux; Marie-Pierre Simon; Jacques Pouysségur Journal: Proc Natl Acad Sci U S A Date: 2011-09-19 Impact factor: 11.205
Authors: Mark G Slomiany; G Daniel Grass; Angela D Robertson; Xiao Y Yang; Bernard L Maria; Craig Beeson; Bryan P Toole Journal: Cancer Res Date: 2009-01-27 Impact factor: 12.701