Expression Of Tyrosine Phosphatase SHP-2 In The Progress Of Colitis To Cancer And Sensitized Effect Of Andrographolide On 5-FU In The Therapy Of Mouse Colon Cancer

Background:Inflammatory bowel disease is one of the causes of colon cancer,but the underlying mechanisms have not been clarified.Protein tyrosine phosphatase SHP-2 plays important roles in the regulation of inflammation as well as tumorigenesis.The resistance of 5-FU was reported partly due to induce the activation of NLRP3 inflammasome and our early study proved that a traditional anti-inflammation drug andrographolide could inhibit the activation of NLRP3 inflammasome.So we examined the expression of SHP-2 in the progress of colitis to colon cancer and investigated the effects of andrographolide in the therapy of colon cancer with 5-FU.Methods:We detected SHP-2 expression in colon cancer cells,mouse colitis-associated cancer induced by AOM+DSS,44 human colitis tissues and 232 human colon cancer specimens,including 58 groups of self-matched adjacent peri-tumor tissues and normal tissues.Besides we observed the combined effects of Andrographolide and 5-FU in CT26 colon cancer xenograft model.Furthermore we detected the activation of NLRP3 inflammasome and proportion change of myeloid-derived suppressor cells(MDSC)by FACS.Infiltration of tumor associated macrophages(TAM)in tumor was tested by Immunofluorescence.IHC was used to examined expression of p-STAT3 and Ki-67.Results:1.We found that compared to the normal colon tissues,SHP-2 significantly increased in colitis tissues,but decreased in tumor tissues.The same results were got in colon tumor cells as well as mice colon.Besides SHP-2 expression was positively associated with tumor differentiation grades and negatively associated with TNM stage.2.Andrographolide could enhance the antitumor effects of 5-FU in mouse CT26 colon cancer xenograft model and significantly prolonged the survival period of the tumor-bearing mice.And in the further study,we proved that andrographolide could inhibit activation of NLRP3 inflammasome induced by 5-FU.Besides,andrographolide enhanced the ability of 5-FU in killing MDSC and TAM,and helped 5-FU inhibit tumor proliferation.Discussion:Clarifying the experssion of SHP-2 in the progress of colitis to cancer will lay significant foundation for further studies on the function and mechanism of SHP-2 in the transformation.SHP-2 may become a diagnosis and prognosis marker of colon cancer.Reversion the 5-FU resistance and increasion its therapy effect by andrographolide established a new road of anti-cancer therapy from the aspect of anti-inflammation and this will bring great benefits to patients.