Mechanism Study On The Promotion Of Colitis-associated Carcinogenesis By High Fat Diet

Colorectal carcinoma(CRC)is one of most common malignant worldwide,with leading morbidity or mortality.With the change of lifestyle,the incidence of CRC in Chinese population has increased significantly.As a recurrent chronic inflammatory disease,inflammatory bowel disease(IBD)prominently increases the risk of CRC.Epidemiological studies have shown that high-fat diet(HFD)is not only a susceptibility factor for IEBD but also a high-risk factor for sporadic colorectal cancer.However,whether the high-fat diet is associated with tumorigenesis and progression of inflammatory-associated carcinoma?What is the underlying mechanism?To pinpoint whether HFD affect colitis-associated carcinogenesis,we established an Azoxymethane(AOM)-Dextran sulfate sodium(DSS)induced colitis-associated carcinoma(CAC)mouse model,following high fat diet or equal-calorie control diet(CD)intervention.It was found that HFD dramatically increased tumor number in mouse colon,and reduced tumor differentiation compared with CD group.But the tumor size was not affected by the diet challenge.In order to investigate whether HFD upregulated CAC incidence by promoting intestinal tract inflammation,we constructed a DSS-induced acute ulcerative colitis mouse model.Unexpectedly,compared with the equal-calorie control diet,HFD didn't aggravate the colitis inflammation injury.The data suggested that HFD promoted tumorigenesis of mouse colon not by exacerbating the inflammatory response.Interestingly,we found that HFD reduced the lipid peroxides level and ferroptosis incidence in mouse CAC model.In addition,HFD or lipid mixture and cholesterol,oleic acid all significantly inhibited ferroptosis in mouse intestinal epithelial cells(organoid model)and human colorectal cancer cells.In vivo,HFD attenuated the inhibition of ferroptosis inducers on transplanted tumors in nude mice.Further study showed that ER stress was closely related to ferroptosis,which could be inhibited by lipids.RNA-Seq data showed that lipid components significantly blocked the upregulation of CHAC1(ChaC glutathione specific gamma-glutamylcyclotransferase 1)induced by RSL3.CHAC1 is a downstream target gene of ER stress and a major enzyme in the cytoplasmic degradation of reduced glutathione(GSH).As expected,lipids inhibited the degradation of GSH and maintained intracellular GSH levels.In summary,HFD significantly enhanced tumorigenesis of CAC in mice.A variety of lipids downregulated CHAC1 by inhibiting the ER stress response,repressed the degradation of reduced glutathione,and suppressed ferroptosis induced by RSL3.Lipids-ER stress-CHAC1-GSH-Ferroptosis signal axis enriched the molecular mechanism of HFD in promoting CAC,and provided a theoretical basis for further understanding tumor formation or development mechanism.