The exosomal integrin α5β1/AEP complex derived from epithelial ovarian cancer cells promotes peritoneal metastasis through regulating mesothelial cell proliferation and migration

Abstract

Purpose Epithelial ovarian cancer (EOC) is one of the most malignant cancers in the gynecologic system. Many patients are diagnosed at an advanced stage with disseminated intra-peritoneal metastases. EOC spreads via both direct extension and transcoelomic spread. However, the interplay between human peritoneal mesothelial cells (HPMCs) and EOC cells is still ambiguous. We hypothesize that integrins (ITG) in HPMCs may play important roles in EOC metastasis. Methods The expression of different integrin subtypes from HPMCs was assessed using Western blotting. The expression of integrin α5β1 (ITGA5B1) and its co-localization with asparaginyl endopeptidase (AEP) in HPMCs derived from EOC patients (EOC-HPMCs) were assessed using immunofluorescence. The role and mechanism of the exosomal ITGA5B1/AEP complex in HPMCs was assessed using both in vitro and in vivo assays. A retrospective study involving 234 cases was carried out to assess ITGA5B1 and AEP levels in circulating sera and ascites of EOC patients, as well as associations between ITGA5B1/AEP expression and overall survival. Results We found that ITGA5B1was highly expressed and co-localized with AEP in EOC cells, and that the exosomal ITGA5B1/AEP complex secreted by EOC cells played an important role in the proliferation and migration of HPMCs. High levels of exosomal ITGA5B1/AEP were also found in circulating sera and ascites of EOC patients, and the expression of ITGA5B1/AEP in EOC tissues was found to be negatively associated with overall survival. Conclusions Our data indicate that EOCs may regulate the function of HPMCs through exosomal ITGA5B1/AEP, which may be crucial for peritoneal metastasis.

Expression and Role of Dickkopf-1 (Dkk1) in Tumors: From the Cells to the Patients

“…Although the 5-year survival rate of patients with ovarian cancer has been stable for the past 20 years, it is still at a low level (30%~40%), making it the deadliest tumor in gynecological tumors. 85,[94][95][96] Because its early clinical symptoms are not obvious, nearly 2/3 of the patients are in the late stage at the time of diagnosis. 97 Most (80%) of the patients who died had epithelial ovarian cancer (EOC).…”

<p>miR-27b Suppresses Tongue Squamous Cell Carcinoma Epithelial–Mesenchymal Transition by Targeting ITGA5</p>

“…A member of the integrin family, ITGA5 often combines with ITGB1 to form integrin α5β1, which serves as a receptor for cell differentiation, cell development, and migration. 11 Altered expression of ITGA5 has been demonstrated in certain cancers, including colorectal, breast, and oral cancers. [12][13][14] In this study, we confirmed that miR-27b was significantly downregulated while ITGA5 was significantly upregulated in TSCC.…”

Downregulation of Snail by DUSP1 Impairs Cell Migration and Invasion through the Inactivation of JNK and ERK and Is Useful as a Predictive Factor in the Prognosis of Prostate Cancer

“…Alternatively, our group has previously shown that Snail expression is regulated by ERK and an autocrine loop involving transforming growth factor beta (TGFβ)/Src/focal adhesion kinase (FAK) complex in thyroid cancer cells [ 28 ]. Similarly, other authors have demonstrated that FAK activation induces Snail expression and enhances mesothelial cell migration, promoting peritoneal metastasis from ovarian cancer [ 54 ]. Moreover, the JNK pathway activates migration by inducing the phosphorylation of paxillin, which is an adaptor protein related to FAK activation in different cancer cells [ 55 , 56 ].…”