CDK8-FOXJ2通过下调SREBP1/SCD1的表达抑制子宫内膜癌发生发展的作用及机制研究

In recent years, the incidence of endometrial carcinoma (EC) is gradually increasing and younger. The main cause of death of patients is invasion and metastasis. As is known to all, epithelial mesenchymal transition is an early key to tumor invasion and metastasis. Recently studies have shown that cancer is a kind of metabolic disease, and metabolic abnormalities/metabolic syndrome is a key factor in the occurrence of endometrial cancer. Abnormal lipid metabolism increased to meet the rapid proliferation of tumor cell metabolism. However, the specific molecular mechanisms of increased lipid metabolism and related regulating mechanism is still not very clear. Our previous research have shown that lipid metabolism related transcription factor sterol response element-binding protein (SREBP1) and its downstream target gene stearoyl-Co A desaturase 1(SCD1) were significantly overexpressed in endometrial carcinoma, and cyclin-dependent kinase 8(CDK8) play a role of tumor-suppressive effects in endometrial carcinoma by downregulating the expression of SREBP1 and its target gene. Moreover, overexpression of CDK8 can upregulate the expression of FOXJ2, the underlying mechanisms are unknown. It has been confirmed that FOXJ2 is involved in epithelial mesenchymal transition, but its role in endometrial carcinoma has not been reported. This study intends to explore the effect and mechanism of FOXJ2 in the occurrence and development of endometrial carcinoma, to clarify the interaction between CDK8 and FOXJ2, and to explore the effects of FOXJ2 on the lipid metabolism related genes. Finally to further clarify the specific regulating mechanism of abnormal lipid metabolism in endometrial carcinoma.

近年子宫内膜癌发病率逐渐上升并呈年轻化趋势，侵袭转移是引起患者死亡的主要原因，上皮间质转化是诱发肿瘤浸润和转移的早期关键事件。近年研究认为癌症是一种代谢性疾病，代谢异常/代谢综合征是子宫内膜癌发生的关键因素。异常增高的脂质代谢是肿瘤细胞快速增殖的代谢标志，但癌细胞中调控脂质生成增多的分子机制仍不十分明确。我们前期研究显示脂代谢转录因子SREBP1及其下游靶基因SCD1在子宫内膜癌组织中显著高表达，CDK8通过抑制SREBP1及其靶基因的表达而在子宫内膜癌中发挥肿瘤抑制作用，过表达CDK8可上调FOXJ2的表达，潜在机制不详。已证实FOXJ2参与上皮间质转化，但其在子宫内膜癌中的作用及机制尚未见报道。本研究拟探讨FOXJ2在人子宫内膜癌发生发展中的作用及机制，阐明CDK8和FOXJ2之间的相互作用，同时探讨FOXJ2对脂代谢相关基因的调节，进一步明确子宫内膜癌中异常脂代谢的具体分子调节机制。

近年子宫内膜癌发病率逐渐上升并呈年轻化趋势，侵袭转移是引起患者死亡的主要原因。近年研究认为癌症是一种代谢性疾病，代谢异常/代谢综合征是子宫内膜癌发生的关键因素。异常增高的脂质代谢是肿瘤细胞快速增殖的代谢标志，但癌细胞中调控脂质生成增多的分子机制仍不十分明确。. 本研究主要探讨FOXJ2在人子宫内膜癌发生发展中的作用及机制，阐明CDK8和FOXJ2之间的相互作用，同时探讨FOXJ2对脂代谢相关基因的调节，进一步明确子宫内膜癌中异常脂代谢的具体分子调节机制。同时，我们探讨了小分子化合物BF175在子宫内膜癌细胞中的作用及机制。. 研究结果显示FOXJ2在正常子宫内膜组织和子宫内膜癌组织中表达水平无明显差异。CDK8 在子宫内膜癌组织表达水平低于正常子宫内膜组织。CDK8和FOXJ2在子宫内膜癌组织中的表达不存在相关性。降低FOXJ2的表达以及CDK8过表达均可以显著抑制子宫内膜癌细胞的增殖、侵袭、迁移等细胞生物学功能。FOXJ2作为核转录因子，通过促进脂质代谢相关的核转录激活因子SREBF1的表达，促进子宫内膜癌脂质生成，从而促进子宫内膜癌的发生发展和侵袭转移；CDK8通过负向调节SREBP1，抑制子宫内膜癌的脂质生成，从而抑制子宫内膜癌的发生发展和侵袭转移。FOXJ2和CDK8共同通过肿瘤脂质代谢通路，分别发挥肿瘤促进作用和肿瘤抑制作用。. BF175是一种合成的小分子化合物，通过抑制SREBP1通路，发挥抗脂质合成的作用。BF175降低子宫内膜癌细胞AN3CA的活性、集落形成能力和迁移能力，诱导细胞自噬和线粒体相关的凋亡。BF175显著下调SREBP及其下游的基因，并降低细胞内游离脂肪酸及总胆固醇的水平。微阵列芯片分析显示在子宫内膜癌细胞中，BF175明显影响脂代谢通路。BF175在子宫内膜癌细胞中的抗肿瘤作用，有望为子宫内膜癌的治疗开辟新途径。