Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma

Yi-Hsiu Chung,Ji-Hong Hong,Chung-Lin Yang,Gigin Lin,Wan-Ling Wang,Cheng-Kun Tsai,Tzu-Chen Yen,Ching-Fang Yu,Fang-Hsin Chen

doi:10.3390/molecules26092573

Abstract

Purpose: By taking advantage of 18F-FDG PET imaging and tissue nuclear magnetic resonance (NMR) metabolomics, we examined the dynamic metabolic alterations induced by liver irradiation in a mouse model for hepatocellular carcinoma (HCC). Methods: After orthotopic implantation with the mouse liver cancer BNL cells in the right hepatic lobe, animals were divided into two experimental groups. The first received irradiation (RT) at 15 Gy, while the second (no-RT) did not. Intergroup comparisons over time were performed, in terms of 18F-FDG PET findings, NMR metabolomics results, and the expression of genes involved in inflammation and glucose metabolism. Results: As of day one post-irradiation, mice in the RT group showed an increased 18F-FDG uptake in the right liver parenchyma compared with the no-RT group. However, the difference reached statistical significance only on the third post-irradiation day. NMR metabolomics revealed that glucose concentrations peaked on day one post-irradiation both, in the right and left lobes—the latter reflecting a bystander effect. Increased pyruvate and glutamate levels were also evident in the right liver on the third post-irradiation day. The expression levels of the glucose-6-phosphatase (G6PC) and fructose-1, 6-bisphosphatase 1 (FBP1) genes were down-regulated on the first and third post-irradiation days, respectively. Therefore, liver irradiation was associated with a metabolic shift from an impaired gluconeogenesis to an enhanced glycolysis from the first to the third post-irradiation day. Conclusion: Radiation-induced metabolic alterations in the liver parenchyma occur as early as the first post-irradiation day and show dynamic changes over time.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide [1,2].While radiotherapy is an integral part of current hepatocellular carcinoma (HCC) treatment protocols, radiationinduced liver disease (RILD) continues to represent a major obstacle to its widespread implementation [3,4]
In experiments conducted in tumor-free animals, the right-to-left ratio of 18F-FDG uptake in the liver parenchyma measured on post-received irradiation (RT) day 3 was 1.13-fold higher in the RT group compared with the no-RT group (1.11 ± 0.10 versus 0.98 ± 0.03, respectively, p < 0.05, Figure S2)
The hepatic expression of the following genes was assessed by qPCR in the post-irradiation phase: (1) Genes involved in glucose metabolism—including phosphoenolpyruvate carboxykinase 1 (PCK1), fructose bisphosphatase 1 (FBP1), glucose-6-phosphatase (G6PC), and pyruvate carboxylase (PC); (2) hypoxia induced factor 1, alpha subunit (HIF-1α), and (3) genes involved in inflammation—including interleukin (IL)-18, IL-1β, and IL-6

Summary

Introduction

While radiotherapy is an integral part of current HCC treatment protocols, radiationinduced liver disease (RILD) continues to represent a major obstacle to its widespread implementation [3,4]. The onset of RILD is clinically characterized by anicteric hepatomegaly, ascites, and elevated serum alkaline phosphatase. The onset of RILD in humans generally occurs three-six months after liver irradiation. Whereas, it traditionally appears at two post-irradiation weeks in rodent models [5,6]. Molecular changes in irradiated tissues have shown to precede overt morphological or physiological alternations [7,8].

Methods

Results

Conclusion