Abstract
BACKGROUND: Despite recent advancements in targeted therapies for hepatocellular carcinoma (HCC), therapeutic resistance continues to limit their clinical efficacy, highlighting an urgent need to identify novel molecular targets involved in disease progression and drug resistance. METHODS: Both gene set enrichment analysis (GSEA) and experimental gene expression analysis were employed to evaluate the role of GTPBP2 expression in HCC clinicopathogenesis using HCC tissue specimens and cell lines. RESULTS: In this study, we reveal for the first time, the critical role of GTP-binding protein 2 (GTPBP2) as a key contributor to HCC progression and resistance to sorafenib treatment. Our findings demonstrate significant overexpression of GTPBP2 in HCC tissues compared to adjacent normal liver tissues, which strongly correlates with advanced tumor stage, increased tumor size, elevated alpha-fetoprotein (AFP) levels, enhanced sorafenib resistance, and poorer patient survival outcomes. Functional studies further confirm that GTPBP2 promotes aggressive tumor behaviors, including enhanced cell migration and invasion. Mechanistically, we uncover a novel function of GTPBP2 in stabilizing the KRAS oncoprotein by competitively binding βTrCP/BTRC, thus inhibiting KRAS ubiquitination and subsequent degradation. Consequently, this stabilization results in elevated activation of crucial downstream signaling pathways, such as p-AKT and p-MEK, which are implicated in tumor growth, metastasis, and drug resistance. CONCLUSIONS: Collectively, our study identifies GTPBP2 as a promising novel biomarker and therapeutic target, providing essential insights into HCC pathogenesis and offering new translational opportunities to overcome treatment resistance and improve patient outcomes.