Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy

Abstract

Healthy colonocytes derive 60 -70% of their energy supply from short-chain fatty acids, particularly butyrate. Butyrate has profound effects on differentiation, proliferation and apoptosis of colonic epithelial cells by regulating expression of various genes associated with these processes. We have previously shown that butyrate is transported across the luminal membrane of the colonic epithelium via a monocarboxylate transporter, MCT1. In this paper, using immunohistochemistry and in situ hybridisation histochemistry, we have determined the profile of MCT1 protein and mRNA expression along the crypt to surface axis of healthy human colonic tissue. There is a gradient of MCT1 protein expression in the apical membrane of the cells along the crypt-surface axis rising to a peak in the surface epithelial cells. MCT1 mRNA is expressed along the cryptsurface axis and is most abundant in cells lining the crypt. Analysis of healthy colonic tissues and carcinomas using immunohistochemistry and Western blotting revealed a significant decline in the expression of MCT1 protein during transition from normality to malignancy. This was reflected in a corresponding reduction in MCT1 mRNA expression, as measured by Northern analysis. Carcinoma samples displaying reduced levels of MCT1 were found to express the high affinity glucose transporter, GLUT1, suggesting that there is a switch from butyrate to glucose as an energy source in colonic epithelia during transition to malignancy. The expression levels of MCT1 in association with GLUT1 could potentially be used as determinants of the malignant state of colonic tissue.

Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas

“…Unexpectedly, when analysing MCT expression in the available adjacent normal epithelium, we found that MCT1 was the least expressed isoform. However, since these normal tissue areas are in the surroundings of tumour cells, we cannot rule out the possibility that these areas are under the influence of [12,14,17]. Our immunohistochemical findings are in agreement with the results of Koukourakis et al [12].…”

“…Although using different antibodies from this previous study, we were also able to detect a high percentage of positive cases for MCT1 expression as well as MCT1 plasma membrane expression in a high number of cases. However, these findings diverge from previous reports, where the authors described a decrease in MCT1 expression in CRC during transition from normality to malignancy [14,17]. Concerning the clinico-pathological data, we found a significant correlation between MCT1 plasma membrane staining and vascular invasion.…”

“…While Lambert et al [14] described a decrease in MCT1 expression during transition to malignancy, Koukourakis et al [12] reported an increase in MCT1 expression in tumour cells, which is supported by the metabolic alterations induced by anaerobic glycolysis. The latter study also assessed the expression of MCT2 and MCT4, finding a strong cytoplasmic expression of MCT2 in cancer cells, but a weak expression of MCT4 in the tumour environment, suggesting a minimal role of this MCT isoform in CRC metabolic homeostasis.…”

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

“…In a related, unpublished study, SLC16A1 expression was significantly altered, and therefore the test was also used to verify the expression in the jejunum in this study. SLC16A1 (fc: 21.87, DON5) had a decreased expression in the jejunum, and it transports monocarboxylates such as butyrate, lactate and pyruvate (Lambert et al, 2002). It has been suggested that effects of DON on membrane transport is a result of specific modulation of the transporters and is not due to cell damage (Maresca et al, 2002), which is supported by our observations, especially because SLC7A10 was upregulated.…”

Inhibition of Monocarboxylate Transporter 2 Induces Senescence-Associated Mitochondrial Dysfunction and Suppresses Progression of Colorectal Malignancies In Vivo

“…Pinheiro and colleagues reported increased expression of MCTs 1, 2, and 4 in colorectal carcinomas (8). However, earlier analysis of healthy colonic tissues and carcinomas revealed a significant decline in MCT1 protein expression during transition from normality to malignancy (9).…”