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Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma

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Abstract

From a metabolic perspective, cancer may be considered as a metabolic disease characterized by reprogrammed glycolytic metabolism. The aim of the present study was to investigate CD147-mediated glucose metabolic regulation in hepatocellular carcinoma (HCC) and its contribution to altered immune responses in the tumor microenvironment. Several HCC cell lines and corresponding nude mice xenografts models differing in CD147 expressions were established to directly investigate the role of CD147 in the reprogramming of glucose metabolism, and to determine the underlying molecular mechanisms. Immunohistochemistry (IHC) analyses and flow cytometry were used to identify the relationship between reprogrammed glycolysis and immunosuppression in HCC. Upregulated CD147 expressions were found to be associated with enhanced expressions of GLUT1, MCT1 in HCC tumorous tissues. CD147 promoted the glycolytic metabolism in HCC cell lines in vitro via the PI3K/Akt/mTOR signaling pathway. A positive correlation existed between a profile of immunosuppressive lymphocytes infiltration and CD147 expression in HCC tissues. Accumulation of FOXP3-expressing regulatory T cells was induced under a stimulation with lactate in vitro. In conclusion, CD147 promoted glycolytic metabolism in HCC via the PI3K/Akt/mTOR signaling pathway, and was related to immunosuppression in HCC.

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Abbreviations

CTL:

Cytotoxic T lymphocyte

CTLA-4:

Cytotoxic T lymphocytes associated protein-4

DAB:

Diaminobenzidine buffer

DC:

Dendritic cell

2-DG:

2-Deoxy-d-glucose

DMEM:

Dulbecco’s modified eagle medium

ECL:

Enhanced chemiluminescence

EGFP:

Enhanced green fluorescent protein

EMMPRIN:

Extracellular matrix metalloproteinase inducer

FACS:

Fluorescence Activated Cell Sorting

FCS:

Fetal calf serum

18F-FDG:

18F-fluorodeoxyglucose

FOXP3:

Forkhead box protein 3

GLUT1:

Glucose transporter 1

HBs Ag:

Hepatitis B surface antigen

HCC:

Hepatocellular carcinoma

HCV Ab:

Hepatitis C virus antibody

HRP:

Horseradish peroxidase

IHC:

Immunohistochemistry

IL-2:

Interleukin 2

LDH:

Lactate dehydrogenase

MCT1/4:

Monocarboxylate transporters 1 and 4

MNC:

Mononuclear cell

MOI:

Multiplicity of transduction

mTOR:

Mammalian target of rapamycin

NIL:

Non-tumor-infiltrating lymphocytes

NK:

Natural killer

NT:

Natural T

OCR:

Oxygen consumption

PBMC:

Peripheral blood mononuclear cell

PBS:

Phosphate buffer solution

PD-1:

Programmed cell death-1

PET/CT:

Positron Emission Tomography/Computed Tomography

PI3K:

Phosphatidylinositol 3-kinase

PVDF:

Polyvinylidene difluoride membranes

RIPA:

Radio-Immunoprecipitation Assay

RPMI:

Roswell Park Memorial Institute

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

ShRNA:

Small hairpin RNA

SPSS:

Statistical software package

SUVmax :

Maximal standard uptake value

TBS:

Tris buffer saline

Teff:

Effector T cell

TGF-β1:

Transforming growth factor

TIL:

Tumor-infiltrating lymphocytes

TNM:

Tumor Node Metastasis

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Acknowledgements

We would like to thank Wenwen Yu at Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) for her assistance in FACS analyses.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81601377, 81501984 and 2018ZX09201015), the Tianjin Natural Science Fund (Grant Nos. 16JCZDJC35200, 17JCYBJC25100, 18PTZWHZ00100 and H2018206600), the Science and Technology Development Fund of Tianjin Education Commission for Higher Education (Grant Nos. 2018KJ057 and 2018KJ061), the Tianjin Medical University Cancer Institute and Hospital Fund (Grant Nos. Y1601, B1605, B1719, Y1805 and Y1810) and the Incubation Project of the National Clinical Research Center for Cancer (Grant No. N14B09).

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Author notes

  1. Xiaofeng Li, Yufan Zhang and Wenchao Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin, 300060, People’s Republic of China

    Xiaofeng Li, Yufan Zhang, Wenchao Ma, Qiang Fu, Jianjing Liu, Guotao Yin, Peihe Chen, Dong Dai, Wei Chen, Xiaozhou Yu & Wengui Xu

  2. Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People’s Republic of China

    Xiaofeng Li, Yufan Zhang, Wenchao Ma, Qiang Fu, Jianjing Liu, Guotao Yin, Peihe Chen, Dong Dai, Wei Chen, Lisha Qi, Xiaozhou Yu & Wengui Xu

  3. Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People’s Republic of China

    Xiaofeng Li, Yufan Zhang, Wenchao Ma, Qiang Fu, Jianjing Liu, Guotao Yin, Peihe Chen, Dong Dai, Wei Chen, Lisha Qi, Xiaozhou Yu & Wengui Xu

  4. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin, 300060, People’s Republic of China

    Lisha Qi

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  1. Xiaofeng Li
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Contributions

XFL and YFZ contributed to the experimental design, the operation of the experiments, data analyses and interpretation of the results in this study. They both contributed to drafting the manuscript. WCM performed the statistical analyses and drafted the manuscript. QF and JJL performed the cellular and immunological experiments. GTY and PHC established the nude mice xenograft models and performed the imaging tests in vivo. DD and WC designed the study and interpreted the results. LSQ and XZY designed the study and reviewed the draft of the manuscript. WGX was responsible for data interpretation and assessing the final content of the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Lisha Qi, Xiaozhou Yu or Wengui Xu.

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Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval and ethical standards

All procedures were performed in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The present study was approved by Hospital Ethic Review Committee of Peking University People’s Hospital (Beijing, China) on June 6, 2017. All protocols involving animals were in strict accordance with institutional guidelines for the care and use of experimental animals and were approved by the animal ethical review committee of Tianjin Medical University and Cancer Institute (Tianjin, China) on August 18, 2018.

Informed consent

All patients provided written informed consent before surgery for use of their specimens for research. Oral informed consent was obtained from the healthy donors at the Tianjin Blood Center to the use of their blood for research purposes.

Animal source

Female BALB/c nude mice (Beijing Vital River Laboratory Animal Technology Co., Ltd) with an average body weight of 18–22 g were purchased and maintained in specific pathogen-free condition for use.

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Li, X., Zhang, Y., Ma, W. et al. Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma. Cancer Immunol Immunother 69, 535–548 (2020). https://doi.org/10.1007/s00262-019-02457-y

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