Exosomal integrin alpha 3 promotes epithelial ovarian cancer cell migration via the S100A7/p-ERK signaling pathway

Abstract

Epithelial ovarian cancer (EOC) is a highly aggressive malignancy with a poor prognosis due to late-stage diagnosis and the lack of reliable biomarkers for early detection. Exosomes, small vesicles involved in intercellular communication, play a critical role in cancer progression by promoting migration, proliferation, and metastasis. This study investigates the role of exosomal proteins in EOC cell migration and identifies potential biomarkers. Exosomes are isolated from the ascites fluid of EOC patients (C-Exos) and benign ovarian disease patients (B-Exos), and mass spectrometry analysis of clinical samples reveals 185 differentially expressed proteins, with integrin alpha 3 (ITGA3) being strongly associated with poor prognosis. ITGA3 is transported via exosomes to recipient EOC cells, where it is released into the cytoplasm and translocated to the cell membrane. This localization enables ITGA3 to activate the intracellular signaling pathways that drive EOC migration. Immunoprecipitation mass spectrometry of clinical samples reveals that ITGA3 may influence EOC migration through the S100A7/p-ERK signaling pathway. Mechanistically, ITGA3 activates ERK signaling through S100A7, promoting cell migration. In vivo, exosomes enriched with ITGA3 facilitates tumor growth and migration, whereas ITGA3 knockdown reduces these effects. These findings suggest that exosomal ITGA3, via the S100A7/p-ERK signaling pathway, promotes EOC cell migration. ITGA3 could serve as a prognostic biomarker and therapeutic target in EOC. Targeting the ITGA3/S100A7 axis may help suppress migration, suggesting a promising strategy to improve EOC patient outcomes.

1. Introduction

Ovarian cancer (OC) is an aggressive and complex disease that originates in the ovaries, the female reproductive organs responsible for producing eggs and hormones [1,2]. Known for its asymptomatic early stages, OC is often referred to as a “silent killer”, as it frequently evades detection until it reaches an advanced stage [3]. Among the various types of OC, epithelial ovarian cancer (EOC) is the most prevalent, accounting for approximately 90% of cases [4,5]. EOC is highly aggressive and is often detected at advanced stages, leading to a poor prognosis and high mortality rates [6]. Given its complexity and heterogeneity, understanding the molecular mechanisms underlying EOC progression is essential. This knowledge could help identify biomarkers crucial for early detection, prognosis, and targeted therapies. Our research focused on unraveling these mechanisms to discover novel biomarkers that could improve patient outcomes through personalized treatment strategies.

In EOC, exosomes, small vesicles ranging from 40 to 200 nm in diameter found in body fluids such as blood, urine, and ascites, are particularly abundant in ascitic fluid and have unique molecular profiles that distinguish them from those in benign ovarian conditions [7]. When released by cells, exosomes are stable structures that encapsulate a variety of molecules, including nucleic acids, proteins, lipids, and metabolites, enabling intercellular communication [8,9]. In cancer, exosomes carry oncogenic factors, such as specific proteins, which contribute to tumor growth, metastasis, and poor clinical outcomes [10]. Exosomes play crucial roles in several cancers, including lung, breast, gastric, and liver cancers, where they aid in cellular signaling and metastatic spread [11,12]. In EOC, these exosomal biomarkers may drive tumor cell migration, invasion, and immune evasion, directly impacting disease progression and patient outcomes.

Among the key proteins found in exosomes, integrin alpha 3 (ITGA3), a member of the integrin family of cell adhesion molecules, has garnered increasing attention because of its involvement in cancer progression. Integrins, including ITGA3, are transmembrane proteins that facilitate cell signaling through two main pathways: ligand-induced conformational changes in their subunits or direct interactions with other proteins that trigger downstream regulatory pathways [13]. These pathways are critical in cancer progression and influence processes such as tumor initiation, proliferation, immune evasion, and resistance to therapies [14–16]. In many tumors, integrins are overexpressed and contribute to metastatic behavior, making them attractive targets for therapeutic intervention.