ArticleJournal of translational medicine2026
A novel secretory protein, circVEGFC-182aa, promotes esophageal squamous cell carcinoma progression by inducing M2 polarization of tumor-associated macrophages via regulating the TGF-β pathway.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundEsophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis, largely due to limited understanding of the tumor microenvironment and a lack of effective targeted therapies. Circular RNAs (circRNAs) have emerged as key regulators in cancer, yet their potential to encode functional proteins that modulate immune cells in ESCC remains poorly understood.
methodsWe analyzed circRNA expression profiles in ESCC tissues using GEO datasets and validated findings in a cohort of 100 patients. The protein-coding potential of circVEGFC was assessed by dual-luciferase reporter assays, mass spectrometry, and Western blotting. Functional roles were investigated using co-culture systems, flow cytometry, and in vitro functional assays. In vivo effects on tumor growth and metastasis were evaluated in xenograft and lung metastasis mouse models. Mechanistic interactions were explored via co-immunoprecipitation and RNA sequencing.
resultscircVEGFC was significantly upregulated in ESCC tissues and its high expression correlated with advanced tumor stage and poor patient survival. circVEGFC encodes a novel 182-amino acid secretory protein, circVEGFC-182aa, which was detected in ESCC cell supernatants. Tumor-derived circVEGFC-182aa directly bound to transforming growth factor-beta receptor II on macrophages, activating the Smad2/3 signaling pathway and driving M2 polarization. This polarization promoted ESCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro, and significantly enhanced tumor growth and lung metastasis in vivo. Blockade of the transforming growth factor-beta pathway reversed these pro-tumorigenic effects.
conclusionOur findings identify circVEGFC-182aa as a previously unrecognized secretory protein that remodels the tumor immune microenvironment by inducing M2 macrophage polarization via transforming growth factor-beta signaling. The circVEGFC/circVEGFC-182aa axis represents a potential prognostic biomarker and a promising therapeutic target for ESCC.
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