Abstract

Circular RNAs (circRNAs) perform critical functions in cancer biology, commonly serving as microRNA (miRNA) sponges to modulate gene expression. Nevertheless, their participation in gut microbiota-driven colorectal cancer (CRC) has yet to be substantially investigated. Fusobacterium nucleatum ( F. nucleatum ), a well-recognized oncogenic bacterium in the human gut, has been implicated in CRC development, but the underlying mechanisms are not fully defined. In this study, we identified a novel circRNA, circPTBP3 , which is the most significantly upregulated circRNA upon F. nucleatum infection, and is significantly upregulated in CRC tissues. CircPTBP3 is preferentially transcribed over its host gene PTBP3 in response to F. nucleatum through activation of the transcription factor ETS1. Functional assays demonstrated that circPTBP3 enhances CRC cell proliferation and tumor growth in vitro and in vivo. Mechanistically, circPTBP3 acts as a molecular sponge for miR-760 , thereby relieving its suppression of the downstream target gene PUM1 . In clinical CRC specimens, circPTBP3 expression showed a positive correlation with F. nucleatum abundance , PUM1 expression, larger tumor sizes, advanced TNM stages, and a negative correlation with miR-760 levels. These findings establish for the first time that circPTBP3 functions as a pivotal mediator of F. nucleatum ‘s oncogenicity, and reveal a novel F. nucleatum – circPTBP3 – miR-760 – PUM1 regulatory axis that promotes CRC progression. CircPTBP3 may serve as a potential biomarker and therapeutic target in F. nucleatum –associated colorectal carcinogenesis.