The Role Of TL1A In Colitis Associated Carcinogenesis

Recently, the connection of inflammation and cancer is under intensestudy, large scale clinical investigation had revealed that inflammation plays avery important role in the development and progression of many kinds ofcancer. Colitis is correlated with colorectal carcinogenesis, namely, colitisassociated cancer(CAC), which accounts for 15% of cause of death in IBDpatients. With the higher incidence rate of IBD, the prevention of long-termcpmplications becomes more and more important.It has shed light that there is an “inflammation- dysplasia- carcinoma”sequential pathological processes, and multiple immune cells, cytokines andother immune mediators involved in the colorectal carcinogenesis.Inflammation and oxidative stress may play a important role in the progress.However, the exact mechanism is not clear.Tumor necrosis factor ligand-related molecule1A(TL1A), is a novelmember of TNF-superfamily, which receptors is death receptor 3(DR3) anddecoy receptor(Dc R3).TL1 A and its receptor influence immune cell, induceintestinal mucosal immune disorders, lead to release of immune mediators andtrigger intestinal inflammation. On the other hand, TL1 A takes part indevelopment of many kinds of cancer through inducing endothelial cellapoptosis. So, to understand the role of TL1 A, we establish the CAC model.Objective: To establish colitis associated cancer mouse model andunderstand the role of TL1 A in the development of CAC.Methods:(1) LCK-CD2-TL1A-GFP Tg mice were identified by RTreal-time PCR.(2) The WT and Tg mice were randomly divided as followed: a.Control/WT group: wild type mice were administered distilled water(n=10); b.AOM/WT group: wild type mice injected with 12.5 mg/kg azoxymethane(AOM)(n=10); c. DSS/WT group: wild type mice were administered 2.5%dextran sulfate sodium(DSS) in distilled water(n=10); d. AOM+DSS/WT:wild type mice were administered 2.5% DSS in distilled water with singledose injection of 12.5 mg/kg AOM(n=10); e. Control/Tg group: wild typemice were administered distilled water(n=10); f. AOM/Tg group: wild typemice with 12.5 mg/kg AOM; j. DSS/Tg group: wild type mice were received2.5% DSS in distilled water(n=10); h. AOM+DSS/Tg group: wild type micewere administered 2.5% DSS in distilled water with single dose injection of12.5 mg/kg AOM(n=10). Mice received 2.5% DSS water for 7days followedby 14 days of regular drinking water. Mice were subjected to four DSS cycles.(3) Severity of colitis was evaluated by changes of Body weight(BW), diseaseactivity index(DAI), colon histology and pathology score in colon.(4) Thetumor is evaluated by size of tumor, number of tumor, rate of mice burdenedtumor and colon histology and pathology score in colon;(5) The expression ofPCNA was detected by immunohistochemistry assay and western blot.(6) Thecorrelation of inflammation,dysplasia and carcinomas is evaluation.Results:(1) The TL1 A transgenic mice were identified by PCR. TheTL1 A DNA located at 192 bp in Tg mice, while it did not express at 192 bp inWT mice.(2) The proof of colitis showed that BW had greater loss in the DSSand AOM+DSS group compared with that in the Control group and AOMgroup. DAI and pathology scores in the DSS and AOM+DSS group werehigher than that of the Control and AOM group, the length of colon wasshorter. The congestion and edema of colon, inflammation infiltration intomucosa superficial layers were much severity in the DSS and AOM+DSSgroup. Meanwhile, inflammation infiltrations were much more severity inDSS/Tg group and AOM+DSS/Tg group when compared to DSS/WT groupand AOM+DSS/WT group, whereas no significant differences were foundbetween the Control group and the AOM group both in Tg or WT mice.(3) Inthe AOM+DSS group, tumor formed in the colon; compared to theAOM+DSS/WT group, the size and number of the tumor increased,thepathology scores were higher and the degree of dysplasia was higher;(4) Thedata detected by immunohistochemistry assay and Western blot showed that,the protein expressions PCNA was increased in the DSS and AOM+DSSgroup compared with that in the Control group and the AOM group, the dataindicated that the level of PCNA increased more obviously in the DSS/Tg andAOM+DSS/Tg group, and no significant differences were found between theControl group and the AOM group both in Tg or WT mice,(5) Inflammationdegree of dysplasia, tumor size was positively correlated.Conclusion: 1 The TL1 A transgenic mouse model for colitis associatedcarcinogenesis establish.2 During carcinogenis, the TL1 A may regulate carcinogenesis bypromoting dysplasia.