Sodium Pump Na + /K + ATPase Subunit α1-Targeted Positron Emission Tomography Imaging of Hepatocellular Carcinoma in Mouse Models.

Si Tang,Jiacong Ye,Xiaochun Yang,Xu Zhang,Guokai Feng,Yan Mei,Chao Zhou,Weiguang Zhang,Wei Fan,Xiaofei Zhang

doi:10.1007/s11307-021-01659-0

Abstract

Positron emission tomography (PET) imaging was not efficiently used in the early diagnosis of hepatocellular carcinoma (HCC) due to the lack of appropriate tracers. Sodium pump Na + /K + ATPase subunit α1 (NKAα1) emerges to be a potential diagnostic biomarker of HCC. Here, we investigated the feasibility of 18F-ALF-NOTA-S3, a PET tracer based on an NKAα1 peptide, to detect small HCC. GEPIA database was searched to obtain the expression characteristics of NKAα1 in HCC and its relationship with the prognosis. PET/CT was performed in orthotopic, diethylnitrosamine (DEN)-induced and genetically engineered HCC mouse models to evaluate the use of 18F-ALF-NOTA-S3 to detect HCC lesions. NKAα1 is overexpressed in early HCC with a high positive rate and may correlate with poor survival. In orthotopic, DEN-induced and genetically engineered HCC mouse models, PET/CT imaging showed a high accumulation of 18F-ALF-NOTA-S3 in the tumor. The tumor-to-liver ratios are 2.56 ± 1.02, 4.41 ± 1.09, and 4.59 ± 0.65, respectively. Upregulated NKAα1 expression in tumors were verified by immunohistochemistry. Furthermore, 18F-ALF-NOTA-S3 has the ability to detect small HCC lesions with diameters of 2-5mm. NKAα1 may serve as a suitable diagnostic biomarker for HCC. 18F-ALF-NOTA-S3 shows great potential for PET imaging of HCC.

Highlights

Liver cancer is a major health threat and results in huge disease burden worldwide
Retrieval results showed that Na+/K+ ATPase subunit α1 (NKAα1) expression is significantly elevated in LIHC (Liver hepatocellular carcinoma) compared to normal liver tissue (Fig. 1a)
According to the original gene expression profiles of Hepatocellular carcinoma (HCC) tumor and non-tumor quantified, in which NKAα1 expression was included in 35 pairs of tumor/none-tumor samples, we observed approximately 94% (33 out of 35) of early-stage HCC with NKAα1 overexpression compared with paired normal liver tissues at the RNA level (Fig. 1b)

Summary

Introduction

Liver cancer is a major health threat and results in huge disease burden worldwide. It ranks sixth for cancer incidence, fourth for cancer deaths and is second leading cause of cancer years of life lost globally in 2015 (Fitzmaurice et al 2017). Hepatocellular carcinoma (HCC) accounts for 75~85% cases of liver cancer (Bray et al 2018). Treatment for HCC patients diagnosed at an early stage (BCLC stage 0 to A) can lead to an average survival of 60 months. Patients with HCC who have advanced or end-stage disease (BCLC stage C and D) at diagnosis have a poor prognosis, with expected median survival time of 6–8 months (stage C) and 3–4 months (stage D) (EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma 2018). Early diagnosis is one of the keys to improving survival for HCC patients

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Discussion

Conclusion