Journal of experimental & clinical cancer research : CR · 2026
Loss of CSE couples with BRAF V600E to fuel thyroid cancer metastatic progression through zinc-dependent activation of the EMT machinery.
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Xu Shichen, Yu Huixin, Wu Hongxun, Pan Zongfu, Xu Jiajie, Zhu Yun, Huang Botao, Cai Gangming, Gu Xiaobo, Yang Min, Pan Donghui, Pan Jie, Wu Jing, Cheng Xian, Bao Jiandong, Zhang Li
Аннотация
BACKGROUND: BRAF V600E, the principal oncogenic driver in papillary thyroid carcinoma (PTC), strongly correlated with lymph node metastasis, yet the underlying molecular mechanisms remain elusive.
METHODS: This study screened effector related to the BRAF V600E mutation and PTC progression through bioinformatics analysis. The precise functional roles and regulatory networks of cystathionine γ-lyase (CSE), a primary hydrogen sulfide (H₂S)-producing enzyme, in thyroid cancer metastasis were then investigated in cell and mice models. Finally, these findings were further validated in a cohort of clinical pathological samples.
RESULTS: We identified that CSE is aberrantly silenced in advanced thyroid cancer. Mechanistically, BRAF V600E-driven MAPK activation upregulates miR-31-5p, which directly targets the CSE 3'UTR to inhibit its translation. The consequent H₂S deficiency disrupts intracellular metallo-homeostasis, triggering intracellular zinc accumulation that stabilizes Zeb1, MMP-2, thereby orchestrating the epithelial-mesenchymal transition (EMT). Critically, the metastatic potential of thyroid cancer cells relies strictly on CSE enzymatic activity. Pharmacological reconstitution of the H₂S pool using exogenous donors effectively bypasses CSE enzymatic deficiency, eliminates excess zinc, and reactivates metastasis-suppressive signaling.
CONCLUSIONS: These findings uncover a novel miR-31-5p/CSE/H₂S/Zinc axis that fuels BRAF-driven progression. These findings provide a compelling mechanistic rationale for utilizing H₂S-based interventions as a potential therapeutic strategy against BRAF-driven thyroid cancer metastasis.
METHODS: This study screened effector related to the BRAF V600E mutation and PTC progression through bioinformatics analysis. The precise functional roles and regulatory networks of cystathionine γ-lyase (CSE), a primary hydrogen sulfide (H₂S)-producing enzyme, in thyroid cancer metastasis were then investigated in cell and mice models. Finally, these findings were further validated in a cohort of clinical pathological samples.
RESULTS: We identified that CSE is aberrantly silenced in advanced thyroid cancer. Mechanistically, BRAF V600E-driven MAPK activation upregulates miR-31-5p, which directly targets the CSE 3'UTR to inhibit its translation. The consequent H₂S deficiency disrupts intracellular metallo-homeostasis, triggering intracellular zinc accumulation that stabilizes Zeb1, MMP-2, thereby orchestrating the epithelial-mesenchymal transition (EMT). Critically, the metastatic potential of thyroid cancer cells relies strictly on CSE enzymatic activity. Pharmacological reconstitution of the H₂S pool using exogenous donors effectively bypasses CSE enzymatic deficiency, eliminates excess zinc, and reactivates metastasis-suppressive signaling.
CONCLUSIONS: These findings uncover a novel miR-31-5p/CSE/H₂S/Zinc axis that fuels BRAF-driven progression. These findings provide a compelling mechanistic rationale for utilizing H₂S-based interventions as a potential therapeutic strategy against BRAF-driven thyroid cancer metastasis.