P-112 Oleic acid promotes the malignant transformation of Kras-mutant colonic organoids via the expansion of tumorigenic stem cells and abnormal Paneth cells through upregulation of NFATc family

Although the five-year survival rate of colorectal cancer (CRC) is significantly high with localized stage (90%), only 38% patients are diagnosed at this stage. Therefore, finding risk factors CRC could prevent disease early Obesity and high-fat diet consumption CRC. In detail, oleic acids (OA) were found to accumulate in adipose tissues obese as well being most common long chain fatty acid dietary lipid. The role OA development still controversary. On other hand, organoids, which can be derived from adult tissue stem cells, miniatures organs. Recent works suggest organoids useful tools dissect mechanisms involved development. current work aims utilize crypt cell-derived how obesity contribute Organoids Lgr5 + -EGFP mice (normal colon control), -EGFP-creER; LSL-KrasG12D (colonic epithelium harbored KrasG12D mutation) AOM/DSS-induced (cancerous control). For in-vitro, impact on malignant transformation Kras-mutant colonic was assessed by MTT proliferation assay, 2D transwell migration invasion irinotecan-resistant test colony formation assay. tumor in-vivo induced subcutaneous engrafting OA-treated NOD/SCID mice. RNAseq done screen some differential expressed genes when treating OA. existence cell abnormal Paneth population demonstrated immunostaining, flow cytometry ELISA. enhanced through increasing proliferation, migration, invasion, drug resistance formation. Besides, engrafted OA-trained Lgr5-Kras possessed larger tumors. represented positive Lgr5-GFP cells upregulated group. Interestingly, there an Lyz /CD24 organoids. This suggested that may promote differentiation progenitor cells. Indeed, treatment ATOH1 GFI1, contributed select between goblet/Paneth enteroendocrine fates. NFAT family, among NFATc3 most, increased upregulation NFATc inhibition proteasomal degradation resulting low expression complex RNF123, USP18 TRIM30A. addition, nuclear translocalization family VIVIT decline stemness markers markers. Finally, we showed NFATc, especially NFATc3, promoting malignancy Our findings NFATc-relating pathway. expansion tumorigenic via induction cell, potential cancer-toward metaplasia exposing level acid. Oleic unfavorable factor cancer. frequent usage OA, benefit cardiovascular diseases, lead latent sensitive individuals.