Colorectal cancer often returns not because the main tumour survives, but because a small population of stem-like cancer cells can resist treatment, seed new growth, and drive aggressive spread.

This study identifies BEX2 as an important suppressor of those dangerous traits.

When BEX2 levels were high, colorectal cancer cells showed weaker stemness, reduced tumour-forming ability, lower drug resistance, and less invasive behaviour.

Mechanistically, the researchers found that BEX2 destabilises MCL1, which in turn dampens Hedgehog signalling, a pathway closely tied to cancer stem cell maintenance.

The findings point to a new molecular route that could be exploited to curb relapse and improve therapeutic response in colorectal cancer.

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 tumours regenerate after therapy.

Previous studies have linked the Hedgehog pathway to stemness control, while MCL1 has been recognised as a survival factor in many malignancies.

Yet how these molecules interact to shape stem-like behaviour 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 signalling in colorectal cancer.

Researchers from The Second Affiliated Hospital, Zhejiang University School of Medicine, together with collaborators from related cancer research centres in Hangzhou and Shaoxing,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 tumour cell self-renewal, invasiveness, chemoresistance, and tumorigenicity, while restoring or increasing BEX2 produces the opposite effect through the MCL1-Hedgehog signalling 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 tumour formation.

Mechanistically, the researchers found that BEX2 binds MCL1 and promotes its ubiquitination and degradation, reducing MCL1 stability.

This weakens Hedgehog signalling, whereas loss of BEX2 stabilises MCL1 and activates the pathway.

Importantly, blocking Hedgehog signalling 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 tumour 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 tumours with stronger stemness potential.

The BEX2-MCL1-Hedgehog axis also suggests more precise intervention strategies: restoring BEX2 activity, destabilising MCL1, or interrupting downstream Hedgehog signalling 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 tumours, but at disabling their most regenerative and treatment-resistant cells.

Source: China Anti-Cancer Association