Expression And Significance Of UGT1A And Its Related Factors Of The Signal Transduction Pathway In Colonic Adenoma And Colonic Adenocarcinoma

BackgroundColonic cancer is a evolved complex process, including multi-stage and involving a variety of genetic changes, which include activation of oncogenes, absence or inactivation of anti-oncogenes. However, the recent studies have found that colonic cancer is not only involving the role of genes-genes, the connection dietary factors-genes and environmental factors-genes with the occurrence of colonic cancer are important. And the latter has become hot spots in many research. As our dietary structure, eating habits and environmental factors are changing, carcinogenic substances around us are growing, and so the capability of the metabolism for the harmful substances becomes more important. UDP-glucuronosyltransferases (UGTs) are important phase Ⅱ metabolic enzymes, which catalyze the conversion of phenols, alcohols, amines and other chemicals to inactive hydrophilic glucuronides that undergo renal and biliary excretion. Many research have been done on the connections between UGTs and certain liver diseases, but UGTs also have been revealed in extrahepatic tissues, such as gastrointestinal tract, gallbladder and bladder. Domestic and foreign research have shown that UGTs down-regulation was connected with the colon carcinogenesis. Now, there are many research of regulation of UGTs activity by exogenous and xenobiotic substances. The regulation of UGTs is less by its inherent signal transduction pathways. Some studies have shown that Keapl-Nrf2-ARE signal transduction pathway is the main pathway to regulate UGTs. Nrf2migrates to the nucleus to regulate of UGT1A. Keapl binds to Nrf2in the cytoplasm to prevent Nrf2nuclear translocation, which negatively regulates Nrf2. Nrf2/Keapl system represents an important mechanism which can adapt to oxidative stress and carcinogenic substances.The Nrf2/Keapl system is dysregulated in lung, head and neck, breast and pancreatic cancers, which connected with cancer development. Keapl-Nrf2dysregulation, Nrf2overexpression and Keap1and Nrf2genes mutations in cancers may participate in tumor development. There are less research of Keapl-Nrf2regulation of UGT1A. And the studies of UGTs were focused on colonic cancer, colonic adenoma as a precancerous lesion has an important role in development of cancer, so UGTs expression in colonic adenomas may provide a new direction to prevent cancer. This study is to investigate the expression of UGT1A, Nrf2, Keapl protein in colonic adenoma and adenocarcinoma, the relationship bewtween their expression and clinical pathological characteristics, and the integrity of the Nrf2/Keap1system, to provide a theoretical basis for mechanisms of colonic cancer development and prevention cancers. Objective:To investigate the expression of UDP-glucuronosyltransferaselA(UGT1A), Transcription factor Erythroid-E2-related factor2(Nrf2) and Kelch-like ECH-associated protein1(Keap1) in normal colonic mucosa, colonic adenoma tissue and colonic adenocarcinoma tissue, and to analyze the relationship bewtween their expression and clinical pathological characteristics,and then to explore their roles in colon carcinogenesis. Methods:UGT1A, Nrf2and Keap1expression was detected in normal colonic mucosa(24cases), colonic adenoma tissue (30cases) and colonic adenocarcinoma tissue (77cases) by immunohistochemistry. Results:The positive rate of UGT1A was83.3%(20/24),80.0%(24/30) and53.2%(41/77) in normal colonic mucosa, adenoma and adenocarcinoma tissue, respectively. The positive rate of latter one was significantly lower than the former two (P<0.05). The positive rate of Nrf2was70.0%(21/30) in colonic adenomas tissue, and in adenocarcinoma tissue was87.0%(67/77), which were significantly higher than in normal colonic mucosa [41.7%(10/24)]. And the positive rate of Nrf2in adenocarcinoma tissue was also higher than in adenoma tissue, P=0.000. The positive rate of Keapl was61.0%(47/77) in adenocarcinoma tissue, which was higher than in normal colonic tissue [54.2%(13/24)],(P=0.040),and lower than in adenoma tissue [70.0%(21/30)],(P=0.002). UGTIA, Nrf2protein expression in colonic adenocarcinoma differentiation stage and lymph node metastasis were not statistically significant (P>0.05), Keapl protein expression in colonic adenocarcinoma differentiation stage was statistically significant (P<0.05).The expression of Nrf2/Keapl had no correlation in colonic adenoma and adenocarcinoma tissue (r=0.067, P=0.723; r=0.042,.P=0.715).Conclusion:The down-regulation of UGTIA and the dysregulation of Nrf2/Keap1system may be associated with colon carcinogenesis.