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Hypoxia-induced modulation of glucose transporter expression impacts 18F-fluorodeoxyglucose PET-CT imaging in hepatocellular carcinoma

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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.

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Acknowledgments

We thank Dr. Sidney Yu from the Department of Nuclear Medicine and Molecular Imaging Singapore General Hospital for advising the PET-CT imaging.

Funding

This study was funded by the grants from the National Medical Research Council of Singapore, National Young 1000 Talents Program of China and Jiangsu Province Education Department, Jiangsu Province “Innovative and Entrepreneurial Team” and “Innovative and Entrepreneurial Talent.”, Key Project of National Natural Science Foundation of China (81730108), Key Project of Zhejiang Province Ministry of Science and Technology (2015C03055), Key Project of Hangzhou Ministry of Science and Technology (20162013A07) and Start-up Grant of HZNU, National Natural Science Foundation of China (81802328).

Author information

Author notes

  1. Hongping Xia, Jianxiang Chen and Hengjun Gao contributed equally to this work.

Authors and Affiliations

  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

    Hongping Xia & Kam M. Hui

  2. Laboratory of Cancer Genomics, National University of Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore

    Hongping Xia, Shik Nie Kong, Amudha Deivasigamani & Kam M. Hui

  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

    Jianxiang Chen, Tian Xie & Kam M. Hui

  4. Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China

    Hengjun Gao

  5. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China

    Ming Shi

  6. Institute of Molecular and Cell Biology, A*STAR, Singapore, 138673, Singapore

    Kam M. Hui

  7. Department of Biochemistry, Yong Loo Lin School of Medicine, National University Singapore, Singapore, 119077, Singapore

    Kam M. Hui

  8. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 169857, Singapore

    Kam M. Hui

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  1. Hongping Xia
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Corresponding authors

Correspondence to Hongping Xia or Kam M. Hui.

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The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Institutional Review Board (IRB) of Sun Yat-Sen University Cancer Center. All procedures performed in studies involving human participants were following the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The animal study was approved by the Institutional Animal Care and Use Committee (IACUC) of SingHealth. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Xia, H., Chen, J., Gao, H. et al. Hypoxia-induced modulation of glucose transporter expression impacts 18F-fluorodeoxyglucose PET-CT imaging in hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 47, 787–797 (2020). https://doi.org/10.1007/s00259-019-04638-4

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