PA Promotes the Development of Endometrial Cancer by Inhibiting KLF4 Expression
Objective To elucidate whether increased palmitic acid(PA)content after obesity can inhibit KLF4 expression through up-regulation of DNMT1/3b,which in turn regulates the biological behavior of endometrial cancer(EC)cells.Methods General data were collected from non-EC control individuals(n=120)and EC patients(n=30)to analyze the differences in obesi-ty-related phenotypes between the two groups;Endometrial tissues from non-EC control individuals(n=20)and cancer tissues from EC patients(n=20)were collected,and the expression of KLF4 and DNMT1/3b was detected by immunohistochemistry in the endometrial tissues;invitro culture of EC cells was carried out;mRNA and protein expression levels of DNMTs/KLF4/MMP2 and other factors in the cells were detected by qRT-PCR and Western blotting.Transwell and scratch assay were used to detect the proliferation,migration and invasion ability of EC cells;An EC hormonal tumor model was constructed in obese mice,and the tumor-forming ability of EC cells or EC cells overexpressing KLF4 was observed in mice.Results The weight,body mass index,plasma LDL and free fatty acid content of EC patients were significantly higher than that of non-cancer subjects(P＜0.05);The percentage of overweight/obese individuals was higher in EC patients than that of non-cancer subjects(73.33％vs.50.00％,P＜0.05);The expression level of KLF4 in tumor tissues of EC patients was significantly lower,and the expres-sion level of DNMT1/3b was significantly higher.The expression level of KLF4 was significantly negatively correlated with the level of FFAs in serum.After PA treatment,the expression level of KLF4 in EC cells was significantly reduced,the expression levels of DNMT1/3b and MMP2 were significantly increased,and the cell migration and invasion ability was significantly en-hanced,with no significant effect on the cell proliferation ability.Up-regulation of KLF4 significantly reduced the expression lev-el of MMP2 and weakened the migration and invasion ability of EC cells;Down-regulation of KLF4 significantly increased the expression level of MMP2 and enhanced the migration and invasion ability of EC cells;PA treatment with concomitant up-regu-lation of KLF4 significantly reversed the promotional effect of PA treatment on the MMP2 expression level as well as migration and invasion ability of EC cells.The expression levels of KLF4 in EC cells were both significantly increased after down-regula-tion of DNMT1 and DNMT3b;PA treatment with simultaneous down-regulation of DNMT1 and DNMT3b,significantly re-versed these results.The tumor-forming ability of EC cells was significantly enhanced in high-fat diet-induced obese mice,whereas tumor-forming ability of EC cells was significantly reduced in high-fat diet-induced obese mice after overexpression of KLF4.Conclusion Increased plasma PA content after obesity promotes endometrial cancer cell migration,invasion,and in vivo tumor-forming ability by inhibiting KLF4 expression through down-regulation of DNMT1/DNMT3b.
万方数据
维普
