Retrospective Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2018; 24(4): 494-503
Published online Jan 28, 2018. doi: 10.3748/wjg.v24.i4.494
Low glucose metabolism in hepatocellular carcinoma with GPC3 expression
You-Cai Li, Chuan-Sheng Yang, Wen-Lan Zhou, Hong-Sheng Li, Yan-Jiang Han, Quan-Shi Wang, Hu-Bing Wu
You-Cai Li, Chuan-Sheng Yang, Wen-Lan Zhou, Hong-Sheng Li, Yan-Jiang Han, Quan-Shi Wang, Hu-Bing Wu, Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
Author contributions: All authors helped to perform the research and wrote the manuscript; Han YJ contributed to the conception and design of the study; Li YC and Yang CS contributed to performing the procedures and data acquisition and analysis; Wang QS and Wu HB critically revised the manuscript for important intellectual content and approved the final version of the article to be published.
Supported by the National Natural Science Foundation of China, No. 81371591.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Institutional Review Board at Nanfang Hospital, Southern Medical University.
Informed consent statement: Due to the retrospective nature of the study, patients were not required to give informed consent.
Conflict-of-interest statement: All authors declare that there are no conflicts of interest to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hu-Bing Wu, MD, Associate Professor, Nanfang PET Center, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, Guangdong Province, China. wuhbym@163.com
Telephone: +86-20-62787317 Fax: +86-20-61642127
Received: October 28, 2017
Peer-review started: October 28, 2017
First decision: November 22, 20107
Revised: December 20, 2017
Accepted: December 27, 2017
Article in press: December 27, 2017
Published online: January 28, 2018
Processing time: 87 Days and 12 Hours
ARTICLE HIGHLIGHTS
Research background

Glypican-3 (GPC3) is a cell surface proteoglycan overexpressed in most hepatocellular carcinomas (HCCs), but not in normal liver tissue, cirrhosis tissue, or paracancerous tissue. Therefore, GPC3 is suggested to be an important target for diagnosis and therapy. Elucidating the relationship between GPC3 expression and glucose metabolism may contribute to a better understanding of the biological role of GPC3 in regulating glucose metabolism. In addition, the research also could be useful to predict the potential utility of GPC3-targeted imaging in the clinic.

Research motivation

In this study, we investigated the relationship between GPC3 expression and glucose metabolism in HCC with an aim to uncover how GPC3 regulates the glucose metabolism in HCCs and predict the potential utility of GPC3-targeted imaging in the clinic.

Research objectives

This study aimed to investigate the relationship between glucose metabolism and GPC3 expression in HCC.

Research methods

A retrospective analysis was performed on 55 HCC patients who had undergone 18F-FDG PET/CT before therapy. Tumour SUVmax and T/N ratio were used to quantify 18F-FDG uptake. The relationship between 18F-FDG uptake and expression of GPC3 and glucose transporter 1 (GLUT1) was analyzed by immunohistochemical analysis. In vitro cellular 18F-FDG uptake was also measured in GPC3-expressing HepG2 and non-GPC3-expressing RH7777 cells to determine the effect of GPC3 on glucose metabolism. The relationships between GPC3 expression and 18F-FDG uptake, GLUT1 expression, tumour differentiation, and other clinical indicators were analysed using spearman rank correlation, and univariate and multiple logistic regression analyses.

Research results

In the present study, we found a phenomenon that the glucose metabolism in the GPC3-expressing HCC tumours is low in the patient study. 18F-FDG uptake in HCC lesions with GPC3 positivity was significantly lower than that of lesions with GPC3 negativity (SUVmax: 6.01 ± 3.55 vs 9.56 ± 5.95, t = -2.341, P = 0.028; T/NT ratio: 2.62 ± 1.55 vs 4.52 ± 2.92, t = -2.597, P = 0.017). Furthermore, multivariate analysis revealed that only the glucose metabolism was significantly correlated with GPC3 expression (P < 0.05), but not other clinical factors. In in vitro cellular uptake experiments, GPC3-expressing HepG2 cells were also found to have low 18F-FDG uptake than that of non-GPC3-expressing RH7777 cells (0.37% ± 0.05% vs 1.03% ± 0.04% of inputted radioactivity, t = -20.352, P < 0.001). Although an inverse trend of relationship was observed between GPC3 and GLUT1 expression, their association did not reach statistical significance (Spearman correlation coefficient = -0.232, P = 0.088).

Research conclusions

GPC3 was reported to play an important role in regulating malignant transformation and promoting the growth of HCC by stimulating the canonical Wnt signalling pathway. Besides, glucose is very important for malignant cell survival and proliferation. Both of them are very important for tumour growth. Therefore, we suggested that there might be a correlation between GPC3 and tumour glucose metabolism. We used 18F-FDG PET/CT for non-invasively measuring tumour glucose uptake in vivo in HCC patients and 18F-FDG uptake assay to measure the cellular glucose metabolism. In conclusion, the expression of GPC3 was observed to be positive in 67.3% (37/55) of HCC patients. The patient study and in vitro cellular uptake assay demonstrated that the glucose metabolism is inversely correlated with the expression of GPC3 in HCC. These results implied that GPC3 may be another underlying factor that contributes to the complex 18F-FDG uptake characteristics in HCCs. We believe that it is helpful for clarifying the mechanism of anti-GPC3 treatment by uncovering how GPC3 regulates the glucose metabolism in HCC. In addition, we found that GPC3 expression was positive in 15/18 (83.3%) of the lesions with negative 18F-FDG uptake. Combining 18F-FDG uptake with GPC3 expression, the total positivity reached 94.5% (52/55). Therefore, we propose that GPC3-targeted PET imaging may improve diagnostic sensitivity for early stage HCC and can serve as an effective complement to 18F-FDG imaging for diagnosing HCC.

Research perspectives

For the future research, we want to investigate the mechanism concerning how GPC3 regulates the glucose and lipid metabolism in HCC. In the previous study, we found 11C-choline, as a probe of lipid metabolism, could be highly taken up by well- and moderately differentiated HCC. So, we deduce that GPC3 may have a potential to promote the lipid metabolism in HCC, which may conversely reduce the glucose metabolism. We want to do further basic research confirm this hypothesis.

ACKNOWLEDGEMENTS

We thank our colleagues at the Nanfang PET Center for manufacturing the radiopharmaceutical reagents and performing the PET/CT scans. We are also grateful to our colleagues in the Department of Hepatobiliary and Pathology, Nanfang Hospital, for providing follow-up data and pathologic diagnoses.