PDF(Pubmed)
Abstract：
Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERRα and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERRα/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERRα and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERRα and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERRα and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERRα and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERRα promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial-mesenchymal transition pathway. Our findings suggest that ERRα and HMGCS1 are potential targets to suppress EC progression.
摘要：
雌激素相关受体α（ERRα）在子宫内膜癌（EC）的进展中起重要作用。然而,ERRα在EC侵袭和转移中的生物学作用尚不清楚。本研究旨在探讨ERRα和3-羟基-3-甲基戊二酰辅酶A合酶1（HMGCS1）在调节细胞内胆固醇代谢以促进EC进展中的作用。通过免疫共沉淀检测ERRα和HMGCS1的相互作用，并通过伤口愈合和transwell小室侵袭试验研究了ERRα/HMGCS1对EC转移的影响。测量细胞胆固醇含量以验证ERRα与细胞胆固醇代谢之间的关系。此外,进行免疫组织化学以确认ERRα和HMGCS1与EC进展相关。此外，该机制通过功能丧失和功能获得试验或辛伐他汀治疗进行了研究.ERRα和HMGCS1的高表达水平促进了细胞内胆固醇代谢，从而形成了invadadopodia。此外，抑制ERRα和HMGCS1的表达在体外和体内显着削弱了EC的恶性进展。我们的功能分析显示ERRα通过HMGCS1介导的细胞内胆固醇代谢途径促进EC的侵袭和转移,依赖于上皮-间质转化途径。我们的研究结果表明，ERRα和HMGCS1是抑制EC进展的潜在靶点。
