<i>LLGL2</i> Inhibits Ovarian Cancer Metastasis by Regulating Cytoskeleton Remodeling via <i>ACTN1</i>

作者全名："Gu, Qiu-Ying; Liu, Yue-Xi; Wang, Jin-Long; Huang, Xiao-Lan; Li, Ruo-Nan; Hua, Linghu"

作者地址："[Gu, Qiu-Ying; Liu, Yue-Xi; Wang, Jin-Long; Huang, Xiao-Lan; Li, Ruo-Nan; Hua, Linghu] Chongqing Med Univ, Affiliated Hosp 1, Dept Gynecol, Chongqing 400016, Peoples R China"

通信作者："Li, RN; Hua, LH (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Gynecol, Chongqing 400016, Peoples R China."

来源：CANCERS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001132439000001

JCR分区：Q1

影响因子：4.5

年份：2023

卷号：15

期号：24

开始页：　

结束页：　

文献类型：Article

关键词：LLGL2; ovarian cancer; tumor metastasis; F-actin; ACTN1

摘要："Simple Summary: Epithelial ovarian cancer (EOC) is the fifth-leading cause of cancer-related deaths in women worldwide and the most lethal gynecologic malignancy. Seventy-five percent of patients are diagnosed at an advanced stage, accompanied by extensive pelvic and abdominal metastases, and thus have a poor prognosis. We first screened for critical genes in EOC in the GEO database. LLGL2 was upregulated in ovarian cancer tissue, while low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients, implying that LLGL2 may function as a tumor suppressor gene. Our data demonstrated that overexpression of LLGL2 inhibited the ovarian cancer cell migration and invasion abilities in vivo and in vitro. Mechanistically, LLGL2 altered the intracellular localization and function of ACTN1 by interacting with ACTN1 and regulating cytoskeleton remodeling to inhibit the invasion and metastasis of ovarian cancer cells.Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor. LLGL2, as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development, LLGL2 regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role of LLGL2 in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involved LLGL2 overexpression and knockdown showed that LLGL2 inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells."

基金机构：National Natural Science Fund; Experimental Research Center of the First Affiliated Hospital of Chongqing Medical University

基金资助正文：We thank the Experimental Research Center of the First Affiliated Hospital of Chongqing Medical University for providing a platform.