Aberrant MCT4 and GLUT1 expression is correlated with early recurrence and poor prognosis of hepatocellular carcinoma after hepatectomy

Hai‐Long Chen,Ming Shi,Hui Tang,Yun‐Qiang Tang,Han‐Yue Ouyang,Peng Jiang,Min‐Ke He,Yong Le,Zi‐Shan Yu

doi:10.1002/cam4.1521

Abstract

The tumor microenvironment is a key determinant of cancer cell biology. The microenvironment is a complex mixture of tumor cells, stromal cells, and proteins, extracellular matrix, oxygen tension, and pH levels surrounding the cells that regulate the tumor progress. This study identified the prognostic factors associated with hepatocellular carcinoma (HCC) and MCT4 and GLUT1 expression levels in HCC specimens. In this study, we analyzed MCT4 and GLUT1 expression levels in tissue samples from 213 patients with HCC by immunohistochemical analyses and in HCC tumor tissues and matched adjacent nonneoplastic tissues by quantitative real‐time PCR. We conducted a prognostic analysis of the overall survival (OS) and time to recurrence (TTR) using immunoreactivity and other common clinical and pathological parameters. All variables with prognostic impact were further analyzed by multivariate analysis. We found that MCT4 and GLUT1 expression levels were significantly higher in tumor tissues than in adjacent nontumor tissues, and they were positively correlated with tumor size. Survival analysis showed that patients with high expression levels of MCT4 or GLUT1 had a poor OS and TTR. In patients with HCC, MCT4 expression was an independent negative prognostic factor for OS (hazard ratio [HR] = 1.617; 95% confidence interval [CI] = 1.102–2.374; P = 0.014), and metabolic indicators were independent prognostic factors for OS (HR = 1.617, 95% CI = 1.102−2.374, P = 0.006) and TTR (HR = 1.348, 95% CI = 1.079−1.685, P = 0.009). Interestingly, patients with positive metabolic indicator expression in tumor cells had a significantly shorter OS and earlier TTR than those with negative metabolic indicator expression in tumor cells in the ≤5 cm and >5 cm subgroups. In summary, using the expression of MCT4 and GLUT1 and their metabolic parameters to determine the metabolic status of tumors is promising for predicting the prognosis of patients with HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, and its morbidity and mortality increase each year [1]
These data indicate that glucose transporter 1 (GLUT1) expression and monocarboxylic acid transporter 4 (MCT4) expression are upregulated during tumorigenesis
We examined the expression of two important transporters, MCT4 and GLUT1, to determine their metabolic status in HCC and assess their prognostic value

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, and its morbidity and mortality increase each year [1]. Many advances in medical technology have been made, but liver cancer treatment commonly comprises surgical resection combined with radiofrequency ablation, interventional embolization, and targeted molecular therapies [2,3,4]. With the exception of the traditional oxidative oxidation of glucose to pyruvate via the mitochondrial tricarboxylic acid cycle, the energy required for cancer cells comes from the anaerobic glycolysis of glucose [8]. In this process, glucose is converted to lactate by lactate dehydrogenase in cancer cells (Warburg effect) [9]. MCT4 is highly expressed in lung cancer, renal cell carcinoma [15], breast cancer [16], and pancreatic cancer [17], and high levels of MCT4 expression are associated with a high apoptotic index [18]

Methods

Results

Conclusion