An increasing body of research suggests that abnormal circRNA expression contributes significantly to cancer development and progression, including CRC. Despite this, the clinical implications and mechanistic roles of novel circRNAs in CRC have not yet been fully elucidated. Candidate circRNAs associated with colorectal cancer were first screened using computational approaches and subsequently confirmed in patient-derived samples by quantitative real-time PCR and in situ hybridization. Functional and phenotypic analyses were then carried out using both cellular models and animal systems to assess the role of circIL4R in colorectal cancer progression, as well as its association with clinicopathological features. To delineate the molecular basis of circIL4R activity, multiple mechanistic assays, including RNA pull-down, fluorescence in situ hybridization, luciferase-based reporter assays, and ubiquitination experiments, were employed. Elevated levels of circIL4R were observed in colorectal cancer (CRC) cell lines as well as in serum and tissue samples from CRC patients. This upregulation showed a strong positive association with more severe clinicopathological characteristics and unfavorable patient outcomes. In functional studies, circIL4R was shown to enhance migration, CRC cell proliferation, and invasion through activation of the PI3K/AKT signaling pathway. At the molecular level, circIL4R expression is controlled by the transcription factor TFAP2C, and it acts as a sponge for miR-761, thereby increasing TRIM29 levels. Elevated TRIM29 then promotes ubiquitin-dependent degradation of PHLPP1, leading to activation of the PI3K/AKT pathway and ultimately driving CRC tumor progression. These results indicate that elevated circIL4R expression contributes to colorectal cancer progression and highlight its potential utility as a biomarker for disease diagnosis and prognosis, as well as a candidate target for therapeutic intervention in CRC.
