{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Esophageal cancer‐related gene 4 (ECRG4), also known as C2ORF40, is emerging as a multifunctional protein that plays a critical role in maintaining tissue homeostasis. In many epithelial‐derived malignancies—including esophageal, breast, colorectal, renal, glioma, and laryngeal cancers—numerous studies have demonstrated that ECRG4 functions predominantly as a tumor suppressor by inhibiting cell proliferation, colony formation, migration, and invasion while inducing cell cycle arrest and apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " In these contexts, mechanistic studies have shown that ECRG4 can up‐regulate cell cycle inhibitors such as p21 and modulate critical signaling cascades—often by suppressing NF‑κB or by interacting with other regulatory proteins—to block cell cycle progression and promote apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ECRG4 expression is tightly controlled by epigenetic mechanisms; aberrant promoter hypermethylation and altered transcription factor binding (for example, Sp1 sites) are frequent events that lead to its downregulation in many tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " This epigenetic silencing often correlates with adverse clinical features and poorer patient prognoses, highlighting its potential as an independent prognostic marker in various cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its intracellular “gate‐keeper” functions, ECRG4 is synthesized as a secreted, cell surface–tethered precursor that undergoes proteolytic processing to release bioactive peptides. These processed products, sometimes referred to as augurin, have been implicated in the regulation of inflammatory responses, innate immune signaling (through interactions with scavenger receptors and Toll‐like receptor complexes), and even in the modulation of neural cell senescence."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": " In models of tissue injury and repair—such as during cutaneous wound healing—ECRG4 appears to regulate fibroblast migration and may function as a “wound termination” factor, thereby contributing to the restoration of homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Notably, while most studies support a tumor‐suppressive role for ECRG4, there are unique settings in which its expression is up‐regulated and may even promote tumorigenesis. For example, in papillary thyroid carcinoma ECRG4 is overexpressed and appears to enhance cell cycle progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", underscoring that the function of ECRG4 is context dependent. Moreover, recent evidence indicates that extracellular vesicles carrying ECRG4 can inhibit glioma cell proliferation by modulating inflammation and angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, the body of literature indicates that ECRG4 acts as a sentinel molecule regulating cell proliferation, apoptosis, inflammatory signaling, and tissue repair. Its frequent inactivation by epigenetic modification in a number of cancers and its association with improved clinical outcomes upon re‐expression further support its promise as a diagnostic and prognostic biomarker—as well as a potential therapeutic target—in precision medicine."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Renaud Sabatier, Pascal Finetti, José Adelaide, et al. 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