Low glucose metabolism in hepatocellular carcinoma with GPC3 expression

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 SUV_max 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 (SUV_max: 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.