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.
Highlights
Epithelial ovarian cancer (EOC) is the most malignant gynecological carcinoma with a high mortality rate and poor prognosis [1]
We showed that Leucine-rich repeat-containing protein 4 (LRRC4) binds to the c-SH2 domain of PIK3R1 to inhibit the activity of PIK3R1 and subsequently disrupts E-cadherindependent collective invasion of ovarian cancer cells mediated by the PIK3R1 signaling pathway
We first examined the expression of LRRC4 in 5 normal ovarian tissues, 11 low-grade serous ovarian cancer (LGSC), 8 low malignant serous ovarian cancer (LMSC), and 17 high-grade serous ovarian cancer (HGSC) samples using Gene Expression Omnibus (GEO) databases
Summary
Epithelial ovarian cancer (EOC) is the most malignant gynecological carcinoma with a high mortality rate and poor prognosis [1]. High-grade serous ovarian cancer (HGSC) accounts for ∼75% of all ovarian cancer deaths due to advanced stage and cancer cell metastasis when patients are diagnosed [2]. Despite considerable efforts to improve early detection and treatment, tumor metastasis remains a major challenge for clinical treatment [4]. Metastasis is a complex and multistep process that requires cancer cells to detach from primary tumors and migrate to distant organs and is responsible for more than 90% of all cancer-associated deaths. EOC mostly metastasizes into the peritoneal cavity as individual cells and clusters by shedding from ovarian cancer instead of spread in haematogenously [5, 6]. Recent studies have revealed that cell-collective metastasis is the primary mechanism for metastasis in ovarian cancer and that cell-cell junction plays a key role in collective cell movement [7, 8]
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