{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nReg4 is a secreted member of the regenerating islet‐derived gene family that is frequently overexpressed in various gastrointestinal and related neoplasms, with early studies demonstrating its up‐regulation in colorectal adenomas, diffuse‐type gastric carcinomas, pancreatic ductal adenocarcinomas, mucinous tumors, neuroendocrine neoplasms, and other lesions. In these settings, Reg4 has been identified as a marker of intestinal metaplasia and secretory differentiation, and its unique structural features—including a calcium‐independent sugar–binding mode—distinguish it from other C‐type lectins. These observations, originating from gene expression profiling and immunohistochemical studies, have established Reg4 as a potentially useful biomarker for a broad spectrum of pre‐malignant and malignant conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctionally, Reg4 acts as more than just a tissue marker; it actively promotes tumor progression by enhancing cancer cell proliferation, survival, migration, invasion, and metastasis. Mechanistic studies have shown that Reg4 can stimulate autocrine and paracrine signaling through activation of pathways such as epidermal growth factor receptor (EGFR)–Akt–AP1 and the β‐catenin–TCF axis, leading to up‐regulation of cell cycle regulators and matrix metalloproteinases. In addition, Reg4 has been implicated in the maintenance of cancer stem cell features and chemoresistance, while there is evidence supporting its role in facilitating peritoneal dissemination of gastrointestinal cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, Reg4’s expression and function are subject to regulation by key transcription factors—such as CDX2 and GATA6—that link its expression to intestinal differentiation, and its up‐regulation has been correlated with specific clinicopathologic subtypes. Elevated serum levels of Reg4 have been proposed as diagnostic and prognostic markers in cancers of the stomach, pancreas, gallbladder, prostate, and even appendiceal mucinous neoplasms. Targeting Reg4 with neutralizing antibodies has demonstrated promising antitumor activity in preclinical models, highlighting its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Meerit Kämäräinen, Kukka Heiskala, Sakari Knuutila, et al. 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