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SPOCK1 promotes colorectal cancer stemness and tumorigenesis by regulating Wnt/β-catenin pathway

ABSTRACT: Colorectal cancer (CRC) rates are increasing worldwide and disease intractability and chemorefractivity remain a significant clinical challenge. Strong evidence demonstrates that CRC arises from mutated normal stem cells, termed cancer stem cells (CSCs) expressing the receptor LGR5, which is a key amplifier of Wnt/β-catenin signaling. New CSC and Wnt-regulating targets have the potential to reduce CRC mortality. Using bioinformatics we identified SPOCK1, a proteoglycan previously linked to gastrointestinal cancer epithelial-mesenchymal transition, as a potential Wnt-associated CRC stem cell target that predicts CRC patient prognosis and therapy response. β-catenin/TCF/LEF reporter assays, Western blot, and immunofluorescence assays in CRC cell lines demonstrated that knockdown or overexpression of SPOCK1 respectively inhibited or activated Wnt/β-catenin signaling, β-catenin nuclear translocation, and relevant downstream transcriptional targets. Colony formation and spheroid assays revealed that SPOCK1 levels strongly modulated CRC growth and stemness in vitro. Moreover, excluding β-catenin nuclear translocation, SPOCK1’s molecular and functional effects were reversible by β-catenin/TCF/LEF inhibitor iCRT3. Finally, SPOCK1’s pro-tumorigenic effect in CRC was confirmed in vivo using a SPOCK1-overexpressing xenograft model and ex vivo using SPOCK1-overexpressing patient-derived organoids – both of which demonstrated a powerful increase in β-catenin nuclear translocation. Overall, our findings position SPOCK1 as a novel target for Wnt/β-catenin-mediated CRC tumorigenesis and stemness, and further studies are warranted.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309532 | GEO | 2025/10/10

REPOSITORIES: GEO

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