下调 ATP5F1D 抑制 mtROS/NLRP3/caspase-1/GSDMD 轴抑制子宫内膜癌焦亡介导的恶性进展。

Downregulation of ATP5F1D inhibits mtROS/NLRP3/caspase-1/GSDMD axis to suppress pyroptosis-mediated malignant progression of endometrial cancer.

机构信息

The First Clinical Medical College of Lanzhou University, Department of Obstetrics and Gynecology, Gansu Provincial Clinical Research Center for Gynecological Oncology, Lanzhou 730000, Gansu, China; Department of Obstetrics and Gynecology, the First Hospital of Lanzhou University, Gansu Provincial Clinical Research Center for Gynecological Oncology, Lanzhou 730000, Gansu, China.

The First Clinical Medical College of Lanzhou University, Department of Obstetrics and Gynecology, Gansu Provincial Clinical Research Center for Gynecological Oncology, Lanzhou 730000, Gansu, China.

出版信息

Int Immunopharmacol. 2024 Sep 30;139:112808. doi: 10.1016/j.intimp.2024.112808. Epub 2024 Jul 28.

DOI:10.1016/j.intimp.2024.112808

PMID:39079199

Abstract

PURPOSE

In developed countries, endometrial cancer (EC) is the most prevalent gynecological cancer and its occurrence is associated with chronic inflammation. ATP5F1D is a subunit of ATP synthase (complex V), as well as the important component of mitochondrial electron transport chain (ETC). ETC play compelling roles in carcinogenesis. To date, little is known about the role of ATP5F1D in EC.

METHODS

ATP5F1D expression was identified in EC tissues and EC cell lines. We evaluated the influence of ATP5F1D on clinical features and prognosis based on TCGA database. The effects of ATP5F1D in EC malignant progression by applying loss-of-function assays in KLE and Ishikawa cell lines were detected by EdU, CCK-8, wound healing, Transwell, and flow cytometry assays. Additionally, electron microscope, LDH release, ELISA, mitochondrial ROS measurement, and Immunofluorescence were performed to demonstrate ATP5F1D can affect the pyroptosis of EC. To observe the anti-tumor effect on ATP5F1D silencing, we established an in vivo human endometrial tumor model using nude mice.

RESULTS

ATP5F1D expression was significantly upregulated in EC and was associated with favorable prognosis. ATP5F1D knockdown inhibited the proliferation, invasion, and migration of EC cells. Similarly, in nude mice, ATP5F1D knockdown suppressed the growth EC cells. Knocking down ATP5F1D lead to decrease the production of mitochondrial ROS (mtROS) and inhibited pyroptosis of EC cells.

CONCLUSION

Downregulation of ATP5F1D as a new therapeutic strategy that could mediate pyroptosis via suppressing mtROS/NLRP3/caspase-1/GSDMD pathway to inhibit EC progression.

摘要

目的

在发达国家，子宫内膜癌（EC）是最常见的妇科癌症，其发生与慢性炎症有关。ATP5F1D 是 ATP 合酶（复合物 V）的亚基，也是线粒体电子传递链（ETC）的重要组成部分。ETC 在致癌作用中发挥着重要作用。迄今为止，人们对 ATP5F1D 在 EC 中的作用知之甚少。

方法

在 EC 组织和 EC 细胞系中鉴定了 ATP5F1D 的表达。我们根据 TCGA 数据库评估了 ATP5F1D 对临床特征和预后的影响。通过在 KLE 和 Ishikawa 细胞系中应用功能丧失测定法，检测了 ATP5F1D 在 EC 恶性进展中的作用，通过 EdU、CCK-8、划痕愈合、Transwell 和流式细胞术测定法进行检测。此外，通过电子显微镜、LDH 释放、ELISA、线粒体 ROS 测量和免疫荧光法证明 ATP5F1D 可以影响 EC 的细胞焦亡。为了观察对 ATP5F1D 沉默的抗肿瘤作用，我们使用裸鼠建立了体内人子宫内膜肿瘤模型。