Globular adiponectin and its downstream target genes are up-regulated locally in human colorectal tumors: ex vivo and in vitro studies.

OBJECTIVE: Low plasma adiponectin levels are linked to obesity, insulin resistance, and the risk of several types of malignancy. Despite the decline in circulating adiponectin concentrations, the increase in the expression of adiponectin receptors AdipoR1 and AdipoR2 is greater in cancerous than in normal colonic tissue. The purpose of this study was to obtain new information regarding local adiponectin signaling in the pathogenesis of colorectal cancer (CRC). METHODS: We characterized the expressions of adiponectin and several of its downstream targets in paired samples of tumor tissue and adjacent noncancerous mucosa in 60 surgical patients with colorectal adenocarcinomas. RESULTS: Adiponectin was expressed in both colorectal tumors and the adjacent mucosa. The expressions of adiponectin mRNA and its globular protein variant (gAd), adiponectin receptor type 1 and 5' AMP-activated protein kinase (AMPK) mRNA were significantly higher in colorectal tumors than in the adjacent mucosa. This finding was accompanied by increased mRNA expression of genes encoding proteins involved in fatty-acid trafficking and oxidation. The potential interference between adiponectin stimulation and AMPK activation through AMPK1 was examined in an in vitro model with the aid of silencing-RNA experiments. Furthermore, AMPK mRNA expression on tumors was positively correlated with a more advanced tumor stage in the patients. CONCLUSION: We propose that the globular adiponectin-AMPK pathway functions in an autocrine manner in colorectal tumors, explaining some of the beneficial changes in cellular oxidative capacity in tumors in favor of tumorigenesis.

mRNA expression of adipocytokines and glucocorticoid-related genes are associated with downregulation of E-cadherin mRNA in colorectal adenocarcinomas.

BACKGROUND: There is a consistently reported relationship between the incidence of colon cancer and obesity. It is thought that adipose tissue, particularly visceral fat, which secretes systemic factors that alter immunological, metabolic and endocrine milieu and promotes insulin resistance by producing adipocytokines, is important in cancer progression. Systemic high concentrations of adipocytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and glucocorticoid metabolism-related genes have been associated with gastrointestinal cancer. However, limited information exists about the expression of these cytokines within tumour tissue. MATERIAL AND METHODS: mRNA expression of TNF-α, IL-6,IL-8, IL-10, IL-1RN, glucocorticoid receptor alpha (GR-α), 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), plasminogen activator inhibitor-1 (PAI-1), Slug, vimentin, Snail and E-cadherin was analysed in paired samples of tumour tissue and normal mucosa in 60 surgical patients for Dukes B and C colorectal adenocarcinomas using quantitative reverse transcription PCR and microarray technology. The mRNA expression level of analysed genes was compared between tumour tissue and normal mucosa from the same patients, and a correlation to mRNA expression of E-cadherin in the same tissue samples was also performed. RESULTS: A highly significant difference in mRNA expression level of several of the analysed genes was observed between tumour tissue and the normal intestinal mucosa. Inverse correlation between mRNA expression of 11ßHSD1, IL-6, GR-α and PAI-1 on one hand and mRNA expression of E-cadherin on the other hand was observed. CONCLUSION: Results show that the adipocytokines and glucocorticoid metabolism-related genes are overexpressed in colorectal adenocarcinomas, and expression of these genes is associated with the downregulation of E-cadherin mRNA, connecting these genes to carcinogenesis and progression of colorectal cancer.