ArticleBiology direct2026
Cancer-associated fibroblasts-derived exosomal circ_0067557 promotes colorectal cancer epithelial-mesenchymal transition via BHLHE40-mediated transcriptional activation of OTUB2.
Article in Biology direct, 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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6 authors.
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Abstract
objectiveThis study aimed to clarify how cancer-associated fibroblast-derived exosomal circ_0067557 (CAF-exo circ_0067557) promotes epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) through BHLHE40-mediated transcriptional activation of OTUB2.
methodsCAF-derived exosomes were isolated and characterized from CRC tissues, while normal fibroblast-derived exosomes were obtained from adjacent normal tissues. The transfer of circ_0067557 was tracked using fluorescence labeling and endocytosis assays. Expression of circ_0067557, BHLHE40, OTUB2, and EMT-related markers was assessed by qRT-PCR, Western blotting, and immunofluorescence. Gain- and loss-of-function models were established to determine the biological role of circ_0067557. RNA sequencing identified OTUB2 as a key downstream target. ChIP-qPCR and dual-luciferase reporter assays were performed to verify BHLHE40 binding to the OTUB2 promoter. RIP and RNA pull-down assays confirmed the interaction between circ_0067557 and BHLHE40. Mouse xenograft and tail vein metastasis models were used to evaluate the oncogenic effects of circ_0067557 in vivo.
resultsCAF-exos successfully delivered circ_0067557 into CRC cells, significantly enhancing their proliferative, migratory, invasive, and EMT capabilities. Mechanistically, circ_0067557 interacted with and recruited BHLHE40, thereby increasing its binding to the OTUB2 promoter and promoting OTUB2 transcription. In vivo experiments further confirmed that circ_0067557 markedly enhanced tumor growth and distant metastasis through the BHLHE40/OTUB2 signaling axis.
conclusionCAF-exo circ_0067557 promotes EMT, invasion, metastasis, and tumor progression in CRC by recruiting BHLHE40 and activating OTUB2 transcription. These findings reveal a novel mechanism by which the tumor microenvironment (TME) regulates cancer cell metastasis.
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