Relapse remains a central challenge in colorectal cancer, even as surgery, chemotherapy, and targeted approaches continue to improve. A major reason is the persistence of cancer stem cells, which possess self-renewal capacity, tolerate treatment pressure, and help tumors regenerate after therapy. Previous studies have linked the Hedgehog pathway to stemness control, while MCL1 has been recognized as a survival factor in many malignancies. Yet how these molecules interact to shape stem-like behavior in colorectal cancer has remained unclear. Earlier work had already suggested that BEX2 may influence colorectal cancer malignancy, but its role in stemness regulation was not fully defined. Based on these challenges, deeper research was needed into how BEX2 controls stemness-related signaling in colorectal cancer.
Researchers from The Second Affiliated Hospital, Zhejiang University School of Medicine, together with collaborators from related cancer research centers in Hangzhou and Shaoxing, reported (DOI:10.20892/j.issn.2095-3941.2025.0120)in Cancer Biology & Medicine in 2026 that BEX2 acts as a suppressor of stem-like traits in colorectal cancer. Their study shows that loss of BEX2 strengthens tumor cell self-renewal, invasiveness, chemoresistance, and tumorigenicity, while restoring or increasing BEX2 produces the opposite effect through the MCL1-Hedgehog signaling axis.
The team combined clinical-data mining with cell and animal experiments to uncover the mechanism. Analyses of TCGA and GEO datasets showed that BEX2 expression was lower in colorectal cancer tissues than in normal tissues, and that lower BEX2 was associated with poorer disease-free survival and stronger expression of stemness-related markers such as CD133 and CD44. In colorectal cancer cell models, knocking out BEX2 increased sphere formation, enlarged the CD133-positive population, elevated stemness regulators including NANOG and OCT4, and enhanced migration, invasion, and resistance to oxaliplatin. Overexpressing BEX2 reversed these effects. In mouse xenograft models, low BEX2 also promoted stronger tumor formation. Mechanistically, the researchers found that BEX2 binds MCL1 and promotes its ubiquitination and degradation, reducing MCL1 stability. This weakens Hedgehog signaling, whereas loss of BEX2 stabilizes MCL1 and activates the pathway. Importantly, blocking Hedgehog signaling or inhibiting MCL1 reversed the stemness-promoting effects seen in BEX2-deficient cells.
The study positions BEX2 not simply as another cancer-associated molecule, but as a functional brake on the stem-like cell state that makes colorectal cancer harder to treat. By linking BEX2 to MCL1 degradation and Hedgehog suppression, the authors propose a biologically coherent model for how tumor aggressiveness, chemoresistance, and recurrence may be restrained at the molecular level.
The practical value of this work lies in its translational potential. If validated in broader patient cohorts, BEX2 could serve as both a biomarker and a therapeutic entry point for identifying high-risk tumors with stronger stemness potential. The BEX2-MCL1-Hedgehog axis also suggests more precise intervention strategies: restoring BEX2 activity, destabilizing MCL1, or interrupting downstream Hedgehog signaling may help suppress relapse-driving cell populations that survive standard treatment. For colorectal cancer, where recurrence and drug resistance remain stubborn clinical problems, this study offers a fresh framework for designing therapies aimed not only at shrinking tumors, but at disabling their most regenerative and treatment-resistant cells.
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References
DOI
10.20892/j.issn.2095-3941.2025.0120
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0120
Funding information
This research was supported by the National Natural Science Foundation of China (Grant No. 81802750, 82072624, and 82102708), Fundamental Research Funds for the Central Universities (Grant No. 226-2024-00176), Zhejiang Provincial Natural Science Foundation of China (Grant No. LMS25H160014), and Zhejiang Provincial Medicine and Technology Projects Grant (Grant No. 2020RC063).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).