From epigenetics to metastasis: Multifaceted roles of lncRNAs in gastric cancer

Abstract

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, largely due to its high metastatic potential and poor prognosis at advanced stages. Epithelial–mesenchymal transition (EMT) is a pivotal biological process that facilitates tumor invasion, dissemination, and therapeutic resistance in GC. In recent years, long non-coding RNAs (lncRNAs) have emerged as critical regulators of gene expression, orchestrating multiple aspects of cancer progression through epigenetic, transcriptional, and post-transcriptional mechanisms. This review provides a comprehensive overview of the current understanding of lncRNA-mediated regulation of EMT and metastasis in gastric cancer. We summarize how lncRNAs function as epigenetic modulators, competing endogenous RNAs (ceRNAs), and molecular scaffolds to regulate EMT-associated transcription factors, signaling pathways, and chromatin dynamics. In particular, key oncogenic pathways such as Wnt/β-catenin, PI3K/AKT, STAT3, and NF-κB are highlighted as major downstream targets of lncRNA activity. Furthermore, we discuss the involvement of lncRNAs in tumor microenvironment remodeling, hypoxia response, angiogenesis, immune regulation, and extracellular matrix reorganization, all of which contribute to metastatic progression. Importantly, dysregulated lncRNA expression is closely associated with clinicopathological features and patient outcomes, underscoring their potential as diagnostic and prognostic biomarkers. In addition, the therapeutic targeting of lncRNAs represents a promising strategy for overcoming metastasis and treatment resistance in gastric cancer. Overall, this review integrates recent advances in the field and provides insights into the complex regulatory networks governed by lncRNAs, highlighting their translational potential in improving GC management.