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Molecular Imaging and Biology

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01-06-2018 | Research Article

Metformin Promotes 2-Deoxy-2-[¹⁸F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase

Authors: Zhengjie Wang, Fei Kang, Yongheng Gao, Yi Liu, Xiaolong Xu, Xiaowei Ma, Wenhui Ma, Weidong Yang, Jing Wang

Published in: Molecular Imaging and Biology | Issue 3/2018

Abstract

Purpose

The early diagnosis of primary hepatocellular carcinoma (HCC) has the potential to lead to significant improvements for the treatment and survival rates of cancer patients. 2-Deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) is often used as a tracer for positive emission tomography (PET) and X-ray computed tomography (CT) imaging of cancer cells; however, [¹⁸F]FDG PET/CT cannot currently be used as an early diagnostic technique for HCC. This is because these cancer cells express high levels of glucose-6-phosphatase (G6Pase) that is responsible for poor cellular retention of [¹⁸F]FDG. Here, we sought to investigate the feasibility of metformin treatment to promote [¹⁸F]FDG uptake in HCC and the mechanism involved.

Procedures

Human SMMC-7721 HCC cells were treated with metformin (up to 10 mM) or FoxO1 siRNA. The transcriptional and expression levels of FoxO1 and G6Pase were determined by quantitative RT-PCR and Western blotting, respectively. The feasibility of using metformin to promote [¹⁸F]FDG uptake was investigated by both in vitro cell uptake analysis and in vivo microPET/CT imaging. Stable doxycycline-inducible cell lines with FoxO1-overexpression (FoxO1-OE) and FoxO1-knockdown (FoxO1-KD) were constructed to evaluate the impact of FoxO1 on G6Pase expression in vitro and [¹⁸F]FDG uptake in vivo.

Results

Treatment of HCC cells with metformin (Met) leads to a dose-dependent reduction in the expression levels of FoxO1 at the protein level, but not at the mRNA level. Met-induced phosphorylation of FoxO1 initiates a reduction in the expression levels of G6Pase mRNA, which results in an overall increase in the uptake of [¹⁸F]FDG into HCC cells and tumors.

Conclusions

We propose that treatment of HCC cells with Met may be a useful strategy for improving the efficacy of [¹⁸F]FDG as a tracer for PET/CT imaging of HCC tumors in patients.

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Title: Metformin Promotes 2-Deoxy-2-[18F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase
Authors: Zhengjie Wang
Fei Kang
Yongheng Gao
Yi Liu
Xiaolong Xu
Xiaowei Ma
Wenhui Ma
Weidong Yang
Jing Wang
Publication date: 01-06-2018
Publisher: Springer International Publishing
Published in: Molecular Imaging and Biology / Issue 3/2018
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-017-1150-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Metformin Promotes 2-Deoxy-2-[¹⁸F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase

Abstract

Purpose

Procedures

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

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