HRD1 attenuates the high uptake of [18F]FDG in hepatocellular carcinoma PET imaging

Abstract

Introduction: Due to individual deviations in tumor tissue uptake, the role of [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) in hepatocellular carcinoma (HCC) diagnosis is limited. β-Hydroxy β-methylglutaryl-CoA reductase degradation 1 (HRD1) plays a key role in clearing misfolded proteins. This study is aimed to investigate the role and mechanism of HRD1 in [¹⁸F]FDG uptake for the diagnosis of HCC.

Methods: HRD1 expression level was detected using immunohistochemical (IHC) staining in 9 HCC patients. [¹⁸F]FDG PET/CT scans were conducted before treatment. [¹⁸F]FDG uptakes in HRD1 overexpressed and knockdown transgenic models were measured by γ-counter and microPET imaging. The GLUT1-HRD1 complex was examined by co-immunoprecipitation and IHC assays. GLUT1 expression in different cell lines, xenograft models and HCC patients was evaluated by Western blot and IHC assays.

Results: HRD1 was highly expressed in the HCC tumors of patients with low [¹⁸F]FDG uptake, while the HRD1 expression was obviously low in the higher [¹⁸F]FDG uptake group. Both in vitro and in vivo studies found that HRD1 significantly inhibited [¹⁸F]FDG uptake in HCC Huh7 cell lines and animal models. Furthermore, the co-location and interaction of HRD1 with GLUT1 were detected, and the results also indicate that HRD1 could induce the degradation of GLUT1 in vitro and in vivo.

Conclusion: HRD1 inhibits the high uptake of [¹⁸F]FDG in HCC tumor cells by inducing degradation of GLUT1, which leads to decreased diagnostic efficiency of [¹⁸F]FDG PET imaging for HCC.

Advances in knowledge: This study suggests that HRD1 inhibits the high uptake of [¹⁸F]FDG in HCC tumor by inducing degradation of GLUT1.

Implications for patient care: HCC diagnosis with [¹⁸F]FDG PET should be accompanied by determination of HRD1 expression, and patients with high tumor HRD1 expression might be unsuitable for [¹⁸F]FDG PET.

Keywords: E3 ubiquitin ligase; Glucose transporter 1; HMG-CoA reductase degradation 1; Hepatocellular carcinoma; [(18)F]fluorodeoxyglucose positron emission tomography.