{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPINK7, also known as esophageal cancer‐related gene 2 (ECRG2), has emerged as a key regulator of epithelial homeostasis. In the esophageal mucosa, SPINK7 is an intrinsic serine protease inhibitor that is part of the normal differentiation program. Its expression promotes barrier integrity and regulates inflammatory responses by limiting proteolytic activity (for example, that of urokinase plasminogen activator) and suppressing the production of pro‐inflammatory cytokines such as thymic stromal lymphopoietin. Loss or depletion of SPINK7 disrupts the epithelial barrier and stimulates gene expression changes that favor allergic inflammation, thereby linking barrier dysfunction with the pathogenesis of disorders like eosinophilic esophagitis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in barrier maintenance, SPINK7/ECRG2 functions as a tumor suppressor in multiple cancers—most notably in esophageal and oral squamous cell carcinomas. A series of studies have shown that SPINK7/ECRG2 inhibits cancer cell proliferation, migration, and invasion by modulating protease cascades (for example, by binding to urokinase-type plasminogen activator and reducing plasmin and matrix metalloproteinase activities), interfering with integrin and related signaling pathways, and promoting apoptosis. Moreover, SPINK7 expression is tightly regulated by various mechanisms including microRNA binding in an allele-specific manner, p53-dependent transcriptional activation following DNA damage, and other post-translational modifications that affect RNA-binding proteins and apoptotic regulators. Genetic variations—such as short tandem repeat polymorphisms within its noncoding regions—have been associated with increased risk, altered prognosis, and differential drug responsiveness in cancer patients. Collectively, these findings indicate that SPINK7/ECRG2 acts as a multifaceted inhibitor of tumor progression by maintaining genomic stability and preventing extracellular proteolysis‐driven invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in the esophagus and tumors, SPINK7 is expressed in healthy skin and has been implicated in cutaneous homeostasis. Its up-regulation in inflammatory skin diseases such as psoriasis and eczema, as well as its altered expression in oral squamous cell carcinoma, underscores its potential as a molecular biomarker for disease staging and prognosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nurit P Azouz, Mario A Ynga-Durand, Julie M Caldwell, et al. 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