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

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.

Keywords: GLUT1; MCT4; hepatocellular carcinoma; prognosis.

Figure 1

IHC characteristics of MCT4 and GLUT1 in HCC specimens. (A, B) IHC assays of MCT4 (A) and GLUT1 (B) expression in tumor (T) and adjacent nontumor tissues (N). (A) MCT4 expression levels in the tumor (T) tissues are significantly higher than those in the adjacent nontumor tissues (N) (40×). The bottom panel shows an enlargement of the indicated area (200×). (B) GLUT1 expression levels in the tumor (T) tissues are significantly higher than those in the adjacent nontumor tissues (N) (40×). The bottom panel shows an enlargement of the indicated area (200×). (C, D) MCT4 (C) and GLUT1 (D) expression levels in tumor (T) tissue are significantly higher than those in adjacent nontumor tissue (N). The IHC H‐scores are shown as mean with range (bars); *** indicates P < 0.01.

Figure 2

Association between the expression levels of GLUT1 and MCT4 with clinicopathological features. (A) IHC staining for GLUT1 and MCT4 in patients with tumor diameters less than or greater than 5 cm. (B, C) Quantitative real‐time PCR was used to determine the relative MCT4 expression in 66 pairs of HCC tumors and matched nontumor tissues, the correlation between tumor size as well as BCLC stage and MCT4 expression levels, and the correlation between tumor size and GLUT1 expression. Each point represents a sample. (B) MCT4 levels in HCC tissues were significantly higher than those in nontumor tissues (left two columns), and MCT4 was more highly expressed (middle two columns) in tumor samples larger than 5 cm in diameter. (C) Similar results were observed for GLUT1 in the same samples. (D) The IHC H‐scores for GLUT1 (left two columns) and MCT4 (right two columns) in patients with tumor diameter less or more than 5 cm. (E) GLUT1 expression level is positively correlated with MCT4 expression (n = 213). The IHC H‐scores are expressed as mean ± standard error of mean (bars); *** indicates P < 0.01, and ** indicates P < 0.05.

Figure 3

Prognostic significance of MCT4 expression and GLUT1 expression. (A, B) HCC patients with high MCT4 expression levels have a poor OS (A) and short TTR (B). (C, D) Kaplan–Meier analysis of the correlation between MCT4 expression in tumor cells and OS in BCLC stages 0–A (C) and stages B–C (D). (E, F) HCC patients with high GLUT1 expression levels have a poor OS (E) and short TTR (F).

Figure 4

Prognostic significance of the metabolic index. (A, B) HCC patients with a high metabolic index have a poor OS (A) and short TTR (B) (n = 213). (C, D) Kaplan–Meier analysis of OS and TTR in patients according to tumor size, with 5 cm as the cutoff value. The OS ratio represents the prognostic significance of the metabolic index in the group with tumor size ≤5 cm (C) and the group with tumor size >5 cm (D). (E, F) The TTR ratio represents the prognostic significance of the metabolic index in the group with tumor size ≤5 cm (E) and the group with tumor size >5 cm (F).