CircSPARC promotes esophageal squamous cell carcinoma through an HNRNPC–EPN2 splicing axis that activates Wnt/β-Catenin signaling

Persistent activation of the Wnt/β-catenin signaling pathway is a key driver of esophageal squamous cell carcinoma (ESCC) progression. Circular RNAs (circRNAs) have emerged as critical regulators of oncogenic signaling in cancer. However, how circRNAs contribute to the sustained activation of Wnt/β-catenin signaling in ESCC is poorly defined. Integrated analysis of self-sequenced and public circRNA datasets revealed elevated expression of circSPARC in ESCC. The functional effects of circSPARC on cell proliferation, migration, and invasion were evaluated through both in vitro and in vivo assays. RNA pull-down, RNA immunoprecipitation (RIP), alternative splicing analysis, RNA antisense purification (RAP), and cell surface protein biotinylation were used to elucidate the molecular mechanism by which circSPARC mediates aberrant Wnt/β-catenin activation in ESCC. This study identifies a circRNA-mediated alternative splicing axis that promotes activation of Wnt/β-catenin signaling and ESCC progression. CircSPARC interacts with HNRNPC, a heterogeneous nuclear ribonucleoprotein involved in RNA processing, to suppress the tumor-suppressive long transcript of epsin 2 (EPN2), thereby impairing clathrin-mediated endocytosis-dependent degradation of the Wnt receptor frizzled 7 (FZD7). This interaction leads to sustained Wnt/β-catenin activation, thus promoting ESCC progression. Conversely, expression of the EPN2 long transcript restores circSPARC silencing-induced inhibition of Wnt/β-catenin signaling and suppresses ESCC cell malignancy both in vitro and in vivo. Clinically, elevated expression of circSPARC in ESCC tissues correlates with poor patient prognosis. These findings reveal a circSPARC-HNRNPC-EPN2 axis that drives persistent Wnt/β-catenin activation through a mutation-independent mechanism. Targeting this pathway in tumors with high circSPARC expression presents a promising therapeutic strategy.