Oral squamous cell carcinoma (OSCC) accounts for more than 90% of oral cancers and remains associated with poor clinical outcomes despite advances in surgery, radiotherapy, and targeted therapies. Resistance to anti-angiogenic treatment remains a major challenge, partly due to vasculogenic mimicry (VM), a process in which aggressive tumor cells form vessel-like networks independently of endothelial cells, thereby supporting tumor growth, invasion, and metastasis.

A recent study in Genes & Diseases journal by researchers from Central South University and Sun Yat-sen University highlights the TNF receptor-associated factor 6 (TRAF6) as a key molecular driver in orchestrating VM within OSCC via regulation of the IL-33/ST2L signaling axis.

Transcriptomic profiling of VM-positive versus VM-negative tumor tissues showed that VM-positive tumors were enriched in inflammatory pathways, and identified IL1RL1, which encodes the IL-33 receptor ST2, as a key VM-associated gene. Elevated ST2 expression was associated with increased VM formation, advanced disease characteristics, and poor patient prognosis, highlighting its potential clinical relevance in OSCC progression.

Further analyses revealed that activation of the IL-33/ST2L pathway promoted malignant phenotypes in OSCC cells, including enhanced proliferation, migration, colony formation, and VM capacity. Mechanistically, the study showed that IL-33/ST2L signaling activated the TRAF6/NF-κB pathway, leading to transcriptional changes that promote EMT and VM formation. Exposure to IL-33 increased NF-κB activation and altered the expression of key EMT markers, including reduced E-cadherin and elevated N-cadherin and vimentin levels. Conversely, silencing IL1RL1 markedly impaired these effects, indicating that IL-33/ST2L signaling is essential for VM development in OSCC. These findings established a direct link between inflammatory signaling, EMT induction, and VM progression in oral cancer cells. Importantly, pharmacological inhibition of TRAF6 effectively blocked NF-κB activation and reversed the pro-tumorigenic effects induced by IL-33/ST2L signaling.

Additionally, the authors identified the hypoxia-inducible factor-1α (HIF-1α) as a key regulator of ST2 expression. Under hypoxic conditions, HIF-1α enhanced IL1RL1 transcription, leading to increased ST2L expression and amplification of IL-33-mediated signaling. These findings reveal a previously unrecognized molecular connection between tumor hypoxia, inflammatory signaling, EMT, and VM formation in OSCC.

To evaluate the therapeutic potential of targeting TRAF6, the researchers employed C25-140, a pharmacological TRAF6 inhibitor. In vitro experiments demonstrated that TRAF6 inhibition suppressed VM formation and EMT-related changes induced by IL-33. The authors further assessed the efficacy of combining TRAF6 inhibition with the anti-angiogenic agent bevacizumab in xenograft models. While bevacizumab alone reduced conventional blood vessel formation, VM structures remained elevated. In contrast, TRAF6 inhibition significantly decreased VM formation, and the combination treatment suppressed overall tumor growth and dramatically reduced both conventional endothelial vessels and mimicry structures compared with anti-angiogenic therapy alone.

In conclusion, this study identifies the IL-33/ST2L/TRAF6/NF-κB axis as a key regulator of vasculogenic mimicry and EMT in OSCC. Suppressing TRAF6-mediated signaling effectively inhibits VM formation, enhancing the therapeutic efficacy of anti-angiogenic treatment. These findings position TRAF6 as a promising therapeutic target for overcoming vascular adaptation mechanisms and improving treatment outcomes in OSCC patients.

Reference
Title of the original paper: TRAF6 inhibition suppresses vasculogenic mimicry in oral squamous cell carcinoma via targeting IL-33/ST2L-induced EMT

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2026.102114

Funding Information:
National Natural Science Foundation of China (No. 81703069, 81700989)
Fellowship of China Postdoctoral Science Foundation (No. 2020M672523, 2021T140747)
Natural Science Foundation of Hunan Province, China (No. 2021JJ31061, 2022JJ30948)

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