URGCP promotes osteosarcoma progression by regulating the ESCRT-III subunit CHMP4B

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents, with a persistently poor prognosis due to limited effective therapeutic targets. Identifying key oncogenic drivers and their regulatory networks is critical for developing novel targeted therapies to improve clinical outcomes. In this study, we aimed to investigate the expression pattern, diagnostic value, and functional role of URGCP in OS, as well as to elucidate its downstream molecular mechanism, specifically focusing on the URGCP-CHMP4B regulatory axis.

Methods: We conducted a bioinformatics analysis of public datasets (Gene Expression Omnibus) to identify the dysregulation and diagnostic value of upregulator of cell proliferation (URGCP) in OS. In vitro functional assays were conducted in URGCP knockdown MG-63 OS cells, including Cell Counting Kit-8 (CCK-8) proliferation assay, flow cytometry-based apoptosis detection, Reverse transcription quantitative real-time PCR (RT-qPCR), and western blotting. A xenograft mouse model was established to validate the in vitro findings. Rescue experiments were conducted by overexpressing charged multivesicular body protein 4B (CHMP4B) in URGCP knockdown cells to decipher the downstream effector of URGCP.

Results: Bioinformatics analyses revealed that URGCP was significantly upregulated in OS tissues and exhibited diagnostic value. Silencing URGCP significantly inhibited OS cell proliferation and induced apoptosis in vitro, and suppressed tumor growth in vivo. Mechanistically, in vitro and vivo URGCP knockdown led to the downregulation of CHMP4B, a core subunit of the endosomal sorting complex required for transport III (ESCRT-III), which is critical for regulating cell proliferation and apoptosis. Crucially, restoring CHMP4B expression in vitro effectively reversed the anti-proliferative and pro-apoptotic effects induced by URGCP silencing.

Conclusion: Our study identifies URGCP as an oncoprotein in OS that exerts its tumor-promoting effects, at least in part, by positively regulating CHMP4B. The URGCP-CHMP4B axis represents a potential therapeutic target for OS treatment.