Frontiers in Oncology (Feb 2020)
LRRC4 Suppresses E-Cadherin-Dependent Collective Cell Invasion and Metastasis in Epithelial Ovarian Cancer
- Chunhua Zhao,
- Chunhua Zhao,
- Chunhua Zhao,
- Chunhua Zhao,
- Chunhua Zhao,
- Xiaoling She,
- Yan Zhang,
- Yan Zhang,
- Yan Zhang,
- Yan Zhang,
- Changhong Liu,
- Changhong Liu,
- Changhong Liu,
- Changhong Liu,
- Peiyao Li,
- Peiyao Li,
- Peiyao Li,
- Peiyao Li,
- Shuai Chen,
- Buqing Sai,
- Buqing Sai,
- Buqing Sai,
- Buqing Sai,
- Yunchao Li,
- Jianbo Feng,
- Jianbo Feng,
- Jianbo Feng,
- Jianbo Feng,
- Jia Liu,
- Yingnan Sun,
- Songshu Xiao,
- Liping Li,
- Minghua Wu,
- Minghua Wu,
- Minghua Wu,
- Minghua Wu
Affiliations
- Chunhua Zhao
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Chunhua Zhao
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Chunhua Zhao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Chunhua Zhao
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- Chunhua Zhao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
- Xiaoling She
- Second Xiangya Hospital, Central South University, Changsha, China
- Yan Zhang
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Yan Zhang
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Yan Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Yan Zhang
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- Changhong Liu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Changhong Liu
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Changhong Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Changhong Liu
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- Peiyao Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Peiyao Li
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Peiyao Li
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Peiyao Li
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- Shuai Chen
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Buqing Sai
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Buqing Sai
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Buqing Sai
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Buqing Sai
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- Yunchao Li
- Second Xiangya Hospital, Central South University, Changsha, China
- Jianbo Feng
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Jianbo Feng
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Jianbo Feng
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Jianbo Feng
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- Jia Liu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Yingnan Sun
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Songshu Xiao
- Third Xiangya Hospital, Central South University, Changsha, China
- Liping Li
- The Affiliated Zhuzhou Hospital of XiangYa Medical School, Central South University, Changsha, China
- Minghua Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
- Minghua Wu
- School of Basic Medical Science, Cancer Research Institute, Central South University, Changsha, China
- Minghua Wu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China
- Minghua Wu
- Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China
- DOI
- https://doi.org/10.3389/fonc.2020.00144
- Journal volume & issue
-
Vol. 10
Abstract
Epithelial ovarian cancer (EOC) is the most malignant gynecological carcinoma and is of a high incidence of death due to detection at late stages when metastasis already occurs. However, the mechanism underlying metastasis of EOC remains unclear. Analysis of the open database and experiments with immunochemistry showed that LRRC4 is lowly expressed in high-grade serous ovarian cancer (HGSC) cells and during EOC metastasis. The 3D cell culture system and the orthotopic ovarian xenograft model infected with LRRC4-containing adeno-associated virus serotype 9 (AAV9) were used to confirm collective invasion and metastasis of cells in vitro and in vivo. Phos-tag SDS-PAGE was used to detect the phosphorylation of LRRC4 and PIK3R1. A number of experiments with methods such as co-immunoprecipitation and immunoblotting were performed to explore the mechanism for the actions of LRRC4 and PIK3R1 in EOC metastasis. An inverse correlation between LRRC4 and E-cadherin expression was detected in the regions of invasion in primary EOC tissues and metastatic ascites. LRRC4 binds to the cSH2 domain of PIK3R1 and inhibits the activity of PIK3R1, without disrupting the physical interactions between PIK3R1 and PIK3CA. LRRC4 inhibits EOC metastasis by targeting E-cadherin-dependent collective cell invasion and does so by inhibiting the PIK3R1-mediated AKT/GSK3β/β-catenin signaling pathway. LRRC4 functions as a tumor suppressor gene to inhibit EOC collective invasion and metastasis in vitro and in vivo and does so by directly binding to the cSH2 domain of PIK3R1 to exert its regulatory function. Our findings provide a potential novel approach for metastasis prognosis and a new strategy for the treatment of EOC.
Keywords
