{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSuprabasin (SBSN) is a secreted protein originally described in stratified epithelia that now emerges as a multifunctional molecule with roles extending beyond epidermal differentiation. In normal tissues, SBSN is implicated in keratinization and may contribute to epidermal homeostasis and disorders such as atopic dermatitis, as highlighted by its expression in various epithelial compartments."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Recent comprehensive reviews further emphasize SBSN’s potential function as a signaling molecule, with aberrant expression linked to poor prognosis in malignancies such as esophageal carcinoma, glioblastoma, and myelodysplastic syndromes, and note that its precise physiological role remains to be fully elucidated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Additionally, in rarer tumors like salivary gland adenoid cystic carcinoma, the underlying molecular mechanisms remain unclear, suggesting that further insights into SBSN function may shed light on pathogenesis across diverse tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, SBSN has been increasingly recognized as a pro-oncogenic factor. In tumor endothelial cells, increased SBSN expression promotes angiogenic potential—enhancing cell migration and tube formation through the activation of the AKT signaling pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similarly, in esophageal squamous cell carcinoma, SBSN overexpression is associated with advanced clinical stage and operates through activation of the Wnt/β‑catenin pathway to stimulate proliferation and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, epigenetic mechanisms contribute to its oncogenic activation; for instance, in lung cancer cells, dosage-dependent regulation by the testis-specific factor BORIS leads to SBSN demethylation and subsequent upregulation, supporting its role in promoting cancer cell growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct oncogenic functions, SBSN appears to mediate adaptive responses to therapeutic stress and contribute to tumor progression. Under exposure to genotoxic agents like ionizing radiation or 5‑azacytidine, SBSN is upregulated in stress‐resistant, low-adherent cancer cell subpopulations via a MEK/ERK-dependent mechanism, suggesting a role in cellular plasticity and therapy resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, extracellular vesicle-mediated transfer of SBSN among glioma cells enhances migration, invasion, and angiogenesis through activation of the NF‑κB pathway, a process that is associated with more aggressive tumor behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Supporting its potential as a clinically relevant biomarker, SBSN expression in bone marrow correlates with high-risk features and poor prognosis in myelodysplastic syndromes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", while broader gene expression profiling studies in vascular cells have identified SBSN among novel determinants potentially linked to adverse vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masahiro Aoshima, Pawit Phadungsaksawasdi, Shinsuke Nakazawa, et al. 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