KLC3 drives gastric cancer progression by stabilizing SLC2A5 to activate MAPK signaling and promote epithelial-mesenchymal transition.

BACKGROUND: Gastric cancer (GC) is associated with poor prognosis due to its intricate molecular mechanisms that drive multiple malignant functions. While KLC3 has been found to be abnormally expressed in various tumors, its specific mechanistic role in GC remains largely unknown. AIMS: This study aimed to elucidate the functional role of KLC3 in GC and to investigate its involvement in regulating the MAPK signaling pathway via SLC2A5. METHODS: The expression of KLC3 was evaluated in GC tissues and cell lines. Functional assays (CCK8, colony formation, wound healing, Transwell) and an in vivo xenograft model were used to assess its role in proliferation, invasion, and migration. Transcriptome sequencing, co-immunoprecipitation, and rescue experiments were employed to uncover the underlying mechanisms. RESULTS: KLC3 was significantly upregulated in GC and associated with poor patient survival. Its knockdown suppressed GC cell growth, invasion, and migration in vitro and in vivo, attenuated EMT, and reduced SLC2A5 expression. Mechanistically, KLC3 interacts with SLC2A5, potentially regulating its membrane localization and stability, and thus activating the MAPK pathway. Crucially, overexpression of SLC2A5 rescued the inhibitory effects of KLC3 knockdown on the MAPK pathway and EMT. CONCLUSION: This study identifies KLC3 as a key oncoprotein that promotes GC progression by modulating the MAPK signaling pathway through a novel interaction with the fructose transporter SLC2A5. The KLC3-SLC2A5 axis may serve as a critical link between cellular motor machinery and metabolic reprogramming in cancer, presenting a promising therapeutic target for GC.