Hongping Xia1,2, Jianxiang Chen3, Hengjun Gao4, Shik Nie Kong5, Amudha Deivasigamani5, Ming Shi6, Tian Xie3, Kam M Hui7,8,9,10,11,12. 1. Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, 211166, China. xiahongping@njmu.edu.cn. 2. Laboratory of Cancer Genomics, National University of Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. xiahongping@njmu.edu.cn. 3. Holistic Integrative Pharmacy Institutes, School of Medicine & Key Laboratory of Elemene Anti-cancer Medicine of Zhejiang Province & Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, 311100, China. 4. Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China. 5. Laboratory of Cancer Genomics, National University of Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. 6. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China. 7. Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, 211166, China. cmrhkm@nccs.com.sg. 8. Laboratory of Cancer Genomics, National University of Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. cmrhkm@nccs.com.sg. 9. Holistic Integrative Pharmacy Institutes, School of Medicine & Key Laboratory of Elemene Anti-cancer Medicine of Zhejiang Province & Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, 311100, China. cmrhkm@nccs.com.sg. 10. Institute of Molecular and Cell Biology, A*STAR, Singapore, 138673, Singapore. cmrhkm@nccs.com.sg. 11. Department of Biochemistry, Yong Loo Lin School of Medicine, National University Singapore, Singapore, 119077, Singapore. cmrhkm@nccs.com.sg. 12. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 169857, Singapore. cmrhkm@nccs.com.sg.
Abstract
PURPOSE: To investigate the molecular mechanisms underlying the variable standard uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging in hepatocellular carcinoma (HCC) and whether hypoxia-induced glucose transporter expression contributes to the progression of HCC and the rate of glycolysis in HCC cells. MATERIALS AND METHODS: Sixteen HCC specimens obtained from patients who underwent pre-treatment staging with 18F-FDG PET-CT imaging were divided into high maximum SUV (SUVmax > 8) and low SUVmax (SUVmax < 5) groups and employed for whole-genome gene expression profiling using GeneChip Human Genome U133 Plus 2.0 Arrays. The relationship between SUVmax and the expression of glucose transporters 1 and 3 (GLUT1 and GLUT3) was further validated using immunohistochemical analysis. The expression of GLUT1 and GLUT3 in different HCC cells under hypoxia and normoxia conditions were monitored by quantitative reverse transcription PCR (RT-qPCR). Glycolysis and FDG uptake by HCC cells were measured using the Seahorse XF glycolysis stress test and 18F-FDG PET-CT imaging. The effect of GLUT1 and GLUT3 on glucose uptake in HCC cells was examined using the fluorescent D-glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) followed by detection of fluorescence produced by the cells using flow cytometry. RESULTS: Glucose transporters are differentially expressed between samples from HCC patients with high and low SUVmax. In particular, over-expression of GLUT1 and GLUT3 in high SUVmax patients was correlated with high glucose uptake and overall survival. The expression of GLUT1 and GLUT3 was significantly induced by hypoxia in different HCC cells. High expression of GLUT1 and GLUT3 in HCC cells were correlated with high rates of glycolysis and 18F-FDG uptake. Therefore, our data suggested that hypoxia-induced glucose transporters expression could result in the variations of 18F-FDG PET-CT imaging and progression of HCC, contributing to more aggressive disease phenotypes like large tumor size, recurrence, and poor survival. CONCLUSION: Over-expression of GLUT1 and GLUT3 significantly increase glucose uptake in HCC cells. Hypoxia-induced glucose transporters expression may therefore be a contributing variable in 18F-FDG PET-CT imaging and progression in HCC.
PURPOSE: To investigate the molecular mechanisms underlying the variable standard uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging in hepatocellular carcinoma (HCC) and whether hypoxia-induced glucose transporter expression contributes to the progression of HCC and the rate of glycolysis in HCC cells. MATERIALS AND METHODS: Sixteen HCC specimens obtained from patients who underwent pre-treatment staging with 18F-FDG PET-CT imaging were divided into high maximum SUV (SUVmax > 8) and low SUVmax (SUVmax < 5) groups and employed for whole-genome gene expression profiling using GeneChip Human Genome U133 Plus 2.0 Arrays. The relationship between SUVmax and the expression of glucose transporters 1 and 3 (GLUT1 and GLUT3) was further validated using immunohistochemical analysis. The expression of GLUT1 and GLUT3 in different HCC cells under hypoxia and normoxia conditions were monitored by quantitative reverse transcription PCR (RT-qPCR). Glycolysis and FDG uptake by HCC cells were measured using the Seahorse XF glycolysis stress test and 18F-FDG PET-CT imaging. The effect of GLUT1 and GLUT3 on glucose uptake in HCC cells was examined using the fluorescent D-glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) followed by detection of fluorescence produced by the cells using flow cytometry. RESULTS: Glucose transporters are differentially expressed between samples from HCC patients with high and low SUVmax. In particular, over-expression of GLUT1 and GLUT3 in high SUVmax patients was correlated with high glucose uptake and overall survival. The expression of GLUT1 and GLUT3 was significantly induced by hypoxia in different HCC cells. High expression of GLUT1 and GLUT3 in HCC cells were correlated with high rates of glycolysis and 18F-FDG uptake. Therefore, our data suggested that hypoxia-induced glucose transporters expression could result in the variations of 18F-FDG PET-CT imaging and progression of HCC, contributing to more aggressive disease phenotypes like large tumor size, recurrence, and poor survival. CONCLUSION: Over-expression of GLUT1 and GLUT3 significantly increase glucose uptake in HCC cells. Hypoxia-induced glucose transporters expression may therefore be a contributing variable in 18F-FDG PET-CT imaging and progression in HCC.
Entities:
Keywords:
18F-fluorodeoxyglucose positron emission tomography-computed tomography; Glucose transporter; Hepatocellular carcinoma; Hypoxia; Standard uptake value
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