In Vitro Exploration of ACTN4 in Oral Cancer: Unraveling the Cytoskeletal Pathways of Invasion, Apoptosis and Angiogenesis Modulation

Abstract

Alpha-actinin-4 (ACTN4) is a non-muscle actin-binding protein that plays pivotal roles in cytoskeletal organization, cell motility, and cancer progression. This comprehensive review examines the multifaceted functions of ACTN4 in oral squamous cell carcinoma (OSCC), focusing on its impact on cytoskeletal remodeling and invasive behaviors. ACTN4 overexpression has been detected in approximately 70% of OSCC cases and is significantly associated with enhanced invasive potential, poor prognosis, and lymph node metastasis. The protein facilitates cancer progression through complex molecular mechanisms involving cytoskeletal reorganization, epithelial-mesenchymal transition (EMT), and activation of key signaling pathways including PI3K/Akt, ERK/GSK-3β/β-catenin, and Wnt/β-catenin cascades. In vitro studies have demonstrated that ACTN4 promotes the formation of specialized ruffle-edge lamellipodia, enhances cell motility, and increases matrix metalloproteinase activity, thereby contributing to extracellular matrix degradation and invasion. The protein localizes at the leading edges of migrating cells and shows enhanced expression in invasive tumor fronts compared to normal oral epithelium. RNA interference-mediated knockdown of ACTN4 significantly reduces invasive potential and cell migration in OSCC cell lines, validating its functional importance in cancer progression. Gene amplification of ACTN4, detected in 24% of cases, serves as an independent prognostic biomarker associated with reduced overall survival and increased risk of late cervical lymph node metastasis. The integration of network pharmacology and artificial intelligence approaches offers promising avenues for discovering ACTN4-targeted therapeutics, with machine learning algorithms enabling virtual screening of compound libraries and prediction of drug-target interactions. These computational approaches, combined with systems biology methodologies, can accelerate the identification of selective ACTN4 inhibitors and optimize their pharmacological properties for clinical translation. The convergence of mechanistic insights from in vitro studies with advanced AI-driven drug discovery platforms positions ACTN4 as a compelling therapeutic target for developing personalized treatment strategies in oral cancer management.