Abstract
Carbohydrate response element binding protein (ChREBP) is a glucose-sensing transcription factor that mediates the induction of glycolytic and lipogenic genes in response to glucose. We investigated the expression patterns of ChREBP and glucose transporters (GLUTs) in human hepatocellular carcinoma (HCC) and their association with HCC progression. ChREBP, GLUT2 and GLUT1 immunohistochemistry were performed on liver tissue array containing normal liver tissue, HCC adjacent tissue and cancer tissue of different HCC stages. The effect of HCC malignancy on protein expression was analyzed with one-way ANOVA. The correlations between protein expressions were analyzed with Pearson Correlation test. We found that ChREBP protein expression tended to be positively correlated to liver malignancy. GLUT2 protein expression was significantly reduced in human HCC as compared to normal liver tissue and its expression in HCC was inversely associated to malignancy (p < 0.001). In contrast, GLUT1 was significantly increased in cancer cells and its expression was positively correlated to malignancy (p < 0.001). Furthermore, GLUT1 expression was positively associated to ChREBP expression (r = 0.481, p < 0.0001, n = 70) but negatively correlated to GLUT2 expression (r = −0.320, p = 0.007, n = 70). Notably, ChREBP-expressing hepatocytes did not express GLUT2 but GLUT1. This is the first report unveiling expressions of ChREBP and GLUT2/GLUT1 and their relations in HCC. The expression patterns are related to malignancy and this information would facilitate evaluation of clinical behavior and treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women
We found that the expression of Carbohydrate response element binding protein (ChREBP) showed a tendency to increase with liver malignancy, but unexpectedly, that GLUT2 protein expression was decreased in cancer cells compared to normal hepatocytes and its expression was negatively associated with advanced stages of HCC
The results showed that GLUT1 but not GLUT2 positive staining could be detected in ChREBP-positive hepatocytes (Fig. 5a c and e)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women. Evidence is accumulating that perturbed cellular metabolism predisposes human to tumor development. Metabolic diseases such as obesity and diabetes are associated with increased risk to develop various cancers [4,5,6]. Many human tumors display a high rate of aerobic glycolysis, de novo fatty acid synthesis and nucleotide biosynthesis [7, 8]. It has been proposed that increased glucose metabolism promotes lipogenesis and nucleotide biosynthesis, and enhances tumor cell growth and proliferation by providing essential synthetic and bioenergetic molecules [9, 10]
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