{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Gastrokine 1 (GKN1) is a stomach‐specific secreted protein that plays a central role in maintaining gastric mucosal integrity, promoting epithelial repair, and suppressing tumorigenesis. In normal gastric mucosa, GKN1 protects and replenishes the surface epithelium and facilitates rapid healing after injury, thereby contributing to mucosal homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the context of cancer, GKN1 is frequently downregulated in Helicobacter pylori–infected tissues and in both intestinal‐ and diffuse‑type gastric cancers; its loss is closely linked with malignant transformation and poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Experimental restoration of GKN1 expression in gastric cancer cells inhibits cell proliferation and invasion while inducing cell‐cycle arrest and apoptosis. Multiple mechanisms have been implicated in its tumor‐suppressive actions. GKN1 can induce endogenous microRNA (miR‑185) that directly targets key epigenetic regulators such as DNMT1 and EZH2, thereby altering chromatin modifications and suppressing oncogenic transcriptional programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, GKN1 modulates major signaling pathways by downregulating the PI3K/Akt and HRas/Raf/MEK/ERK cascades, restoring epithelial markers (e.g., re‐expression of E‑cadherin) and thus inhibiting epithelial‑to‑mesenchymal transition (EMT) and cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, through its interactions with c‑myc and telomere‑associated proteins, GKN1 promotes telomere shortening and triggers senescence followed by apoptosis, providing an additional layer of growth control in gastric epithelial cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Emerging evidence also indicates that GKN1 can be secreted via exosomes, serving as an intercellular messenger that mediates anti‑proliferative and pro‑apoptotic effects in recipient gastric cancer cells. These exosome‑mediated pathways further underscore the potential of GKN1 as a therapeutic agent and a diagnostic biomarker for early and advanced gastric cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Finally, domain‐mapping studies have demonstrated that the NH₂‑terminal hydrophobic region together with the BRICHOS domain of GKN1 are sufficient to recapitulate its tumor‑suppressive functions, suggesting these domains as candidates for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, GKN1 functions as a multifunctional protein that preserves gastric epithelial integrity, regulates key signaling and epigenetic pathways to inhibit proliferation, migration, and EMT, and ultimately acts as a potent tumor suppressor in the stomach. Its loss not only contributes to gastric carcinogenesis but also represents a promising target for early diagnosis and therapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emilia Rippa, Giovanna La Monica, Rosa Allocca, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The tumor suppressor gastrokine-1 is expressed in placenta and contributes to the regulation of trophoblast migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Placenta (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.placenta.2013.08.005"}], "href": "https://doi.org/10.1016/j.placenta.2013.08.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23993393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23993393"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Steven F Moss, Jin-Woo Lee, Edmond Sabo, et al. 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