Palmitic acid activates GPRs/KLF7/HEY1 signal axis to promote the occurrence and development of endometrial carcinoma

Abstract Background: Our previous study found that the increase of palmitic acid (PA) in serum after obesity is closely related to the development of endometrial cancer (EC), and the high concentration of PA can promote the biological behavior of EC cells by up-regulating the expression of KLF7, but the specific molecular mechanism are unclear. Methods: EC cells Ishikawa were treated with high concentrations(20μM and 50μM) of PA, the effects on the proliferative ability of Ishikawa cells were examined by CCK-8 and colony formation assay, and on the invasive and migratory ability of Ishikawa cells by transwell and scratch assay. RNA-Seq combined with double luciferase reporter gene experiment were used to confirm the key downstream target gene for KLF7. Constructing the model of obese mice with EC tumor, and collecting the endometrial tissues of EC patients and non-cancer individuals,we validated a possible molecular mechanism by which PA upregulation of KLF7 promotes EC development in vivo. The mRNA and protein expression levels of GPR40/120, KLF7 and HEY1 were detected in EC cells and tumor tissues by qRT-PCR and western-blot. Results: High concentrations of PA can up-regulate the expression of KLF7 through GPR40/120 and promote the biological behavior of EC cells. HEY1 may be a key downstream gene for KLF7 to promote the progression of EC. Under the state of obesity, the tumorigenesis ability of EC cells in mice was enhanced, and the expression of GPR40/120, KLF7 and HEY1 in tumor tissue increased. Up/down regulation of KLF7 can significantly enhance/weaken the tumorigenic ability of EC cells and promote/inhibit the expression of HEY1 in tumor tissues. The expression level of KLF7 and HEY1 in tumor tissues of EC individuals were significantly higher than that of non-cancer individuals. Conclusions: Increased PA content after obesity promotes the development of EC by activating the GPRs/KLF7/HEY1 signaling axis.