BEX2 influences the MCL1-Hedgehog signaling axis to regulate the potential of stemness characterization in colorectal cancer

作者：Yucheng Qian, Jingsun Wei, Yuan Bian, Yinuo Tan, Yimin Fang, Liubo Chen, Kai Jiang, Dongliang Fu, Xiaoxu Ge, Tianyi Ling, Qian Xiao, Kefeng Ding, Yeting Hu · 发表于：Cancer Biology and Medicine · 年份：2026 · DOI：10.20892/j.issn.2095-3941.2025.0120 · 被引用次数：1 · 研究领域：Hedgehog Signaling Pathway Studies、Cancer-related Molecular Pathways、Cancer Cells and Metastasis

Objective: Colorectal cancer (CRC) progression is driven by cancer stem cells (CSCs) that evade treatment through dynamic phenotype modulation. Our previous research identified BEX2 as a significant regulator of CRC malignancy involving the Hedgehog (Hh) pathway. This study aimed to elucidate the influence of BEX2 on CRC stemness and the interaction with the Hh signaling pathway, potentially uncovering innovative therapeutic strategies for combating CRC. Methods: TCGA and GEO data were analyzed to correlate BEX2 expression with clinical outcomes and stemness markers in CRC. Functional assays, including spheroid formation, flow cytometry, extreme limiting dilution assay (ELDA), Transwell, wound healing, and cell viability assay, were performed in DLD1 and HCT116 cell lines. Immunoblotting and qRT-PCR assessed BEX2 expression with in vivo validation in NOD/SCID mice. Results: The findings revealed a negative correlation between BEX2 expression and the levels of stemness-associated genes with a significant association with CRC patient’ prognosis. Overexpression of BEX2 diminished CRC stemness potential, whereas BEX2 knockdown led to a pronounced enhancement of these stem-like characteristics. Further investigation revealed that BEX2 inhibited the Hh pathway. BEX2 interacted with MCL1, promoting ubiquitination and degradation, thereby decreasing MCL1 stability. Low BEX2 expression stabilized MCL1, which enhanced stemness potential. These results suggested BEX2 modulate...