The Study Of The Roles Of CUEDC2in Colitis-associated Cancer

Colorectal cancer is the third cancer killer worldwide, and the second cancer inthe developed countries, such as USA. Moreover, the morbility is annually increasing.More than1,000,000colorectal cancers are newly developed worldwide. Only about20%patients have family disease history, the other colorectal cancers are caused byenvironments, special intestinal commensal bacteria and chronic intestinalinflammation. The chronic intestinal inflammation has been concerned by researchersin recent years.The most common chronic intestinal inflammation associated with colorectalcancer is inflammatory bowel disease, consisting of ulcerative colitis and crohn’sdisease. Over20%patients with colitis for thirty years developed to colitis-associatedcancer, and more than50%patients died of CAC. Younger the patients, more severerthe inflammation, and more dangerous the canceration. The colorectal cancer causedby inflammatory bowel disease is referred as colitis-associated cancer.Colitis-associated Cancer is mainly caused by aggravating inflammation boweldisease with immunological dysfunction and NF-κB and JAK/STAT3abnormallyactivation. A great quantity of inflammation cells and proinflammation cytokines inintestine, such as TNFα，IL-6, IL-17, IL-23, activate reactive oxygen species andreactive nitrogen intermediates and change the biological processes including cellulargrowth, apoptosis, proliferation，and so on. Furthermore, the consistent chronicinflammation also induces the dysregulation of signaling pathway such as Wnt, p53,K-ras,TGFα, finally leading to the tumor development.CUEDC2is a type of protein containing CUE-domain, which is overexpressedin many tumors, like kidney cancer, ovary cancer and brain cancer. CUEDC2caninteract with IKKα and IKKα and repress the activation of the transcription factorNF-κB by decreasing phosphorylation and interaction of IKKα and IKKβ Furthermore, CUEDC2can function collaboratively with SOCS3to inhibitJAK1/STAT3signaling by increasing SOCS3stability. NF-κB and STAT3are boththe main transcription factors induced by many cytokines, and the activation ofNF-κB and STAT3promotes the expression of series of antiapoptotic and proliferative genes, which is quite important for the survival of major cells. Except forparticipating in the process of inflammation, cancer and immunity, CUEDC2alsoimpact on chromosome stability and cancer development. Therefore，since CUEDC2makes function in inflammation and cancer, it might be a new cue to study themechanism of inflammation-induced-cancer.Animal model can simulate person’s disease, which is significant to study themolecular mechanism of diverse diseases. Azoxymethane is a kind of carcinogenicchemical. After its products of metabolism were disassembled by intestinal microbia,they play roles in carcinogenesis by inducing mutation and damage. Dextran sodiumsulfate is a kind of pro-inflammation chemical reagents, which caused colitis bydamaging the intestinal barrier, imbalacing the intestinal bacteria and dysfunctioningthe macrophage. Just because the AOM/DSS model can remodel thepathophysiological process of inflammation-induced-cancer in intestine, recently it isused to explore the mechanism of CAC.In our study, CAC model induced by AOM/DSS were established using differentgenotype mice. The mice weight, stool consistency and stool blood were observed andanalyzed during the colorectal cancer processesing. Finally，in CUEDC2^-/-CAC mice,the tumor number, tumor size and tumor load are all more than that of wild type mice,moreover，the weight loss, diarrhea and stool blood are all severer than that of DSSmodel.In order to further inquire the cause of more tumor load in CUEDC2^-/-CACmodel, the proinflammation cytokines TNFα、 IL-6、 COX2and PGE2, andchemokines MIP2and MCP1were detected in the tissues of colitis and colorectalcancer. At last, these cytokines and chemokines were increased in CUEDC2^-/-CACmodel. At the same time, some proliferative indexes Ki67, BrdU and Cyclin D1wereanalyzed using immunohistochemical test. On the result, these proliferative indexesare all higher in CUEDC2^-/-colitis and cancer model than that of wild type model.Then, for revealing the mechanism of excessive cell proliferation in CUEDC2knockout mice, in DSS-colitis model, the colitis tissues of two genotype mice werewestern blotted. We find that the IKKα/β and STAT3consistent phosphalation inCUEDC2^-/-mice, however, dephosphalation of IKKα/β and STAT3occurred in wildtype mice during the colitis recovery stage. So, more tumor load in CUEDC2^-/-CACmodel was resulted in through modulating NF-κB and STAT3signaling pathway,with IKKα/β and STAT3consistent phosphalation. In conclusion, CUEDC2plays roles in inflammation-induced-cancer as asignificant functional gene. The stable CUEDC2expression in intestine can protectinflammation from developing to tumor through suppressing NF-κB and STAT3activation and inflammatory cytokines’ expression. Consequently，this result applies acue to molecular mechanism for inflammation-induced tumor. CUEDC2might be amarker to evaluate the colitis severity and estimate the prognosis.