{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSyndecan‐2 (SDC2) is a multifunctional transmembrane heparan sulfate proteoglycan that modulates cell adhesion, migration, and proliferation in various malignancies. In colon cancer cells, high SDC2 expression promotes cell adhesion and cytoskeletal organization—processes that underlie enhanced proliferation and tumorigenic activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In endothelial cells, inflammatory stimuli upregulate SDC2 and its ectodomain can bind chemokines such as interleukin‐8, thereby contributing to the integration of adhesion and inflammatory signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In melanoma, increased SDC2 expression drives cell migration and invasion, while in colon adenocarcinoma SDC2 promotes Rac‐dependent migration through mechanisms involving Tiam1 recruitment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " Moreover, studies in fibrosarcoma and pancreatic adenocarcinoma implicate SDC2 in processes such as metastatic spread and perineural invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct role in modulating cell behavior, aberrations in the SDC2 gene are emerging as valuable biomarkers. Promoter hypermethylation of SDC2 has been shown to serve as a highly sensitive and specific marker for early colorectal cancer detection in both tissue and blood‐based assays."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " Differential methylation of SDC2 is also observed in human papilloma virus–associated head and neck squamous cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and comprehensive genetic screens have implicated SDC2 variants in developmental malformations such as nonsyndromic cleft lip with or without cleft palate."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In esophageal squamous cell carcinoma, SDC2—functionally integrated into transforming growth factor–beta (TGF‐β) signaling networks—correlates with disease aggressiveness"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", whereas in colorectal cancer its pivotal roles in tumor development and progression are firmly established."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Finally, in prostate cancer, relative stability of SDC2 expression compared to other syndecans suggests a distinct, context‐dependent role in tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, SDC2 exerts its effects through multiple types of interactions. Biophysical studies reveal that its transmembrane domain dimerizes very strongly—a feature that is required for proper receptor complex formation and the initiation of downstream signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Its cytoplasmic tail engages intracellular effectors such as syntenin‐1 to activate Rac and direct cytoskeletal reorganization, which is central to enhanced cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " In addition, SDC2 functions as a ligand for the protein tyrosine phosphatase receptor CD148, thereby modulating β1 integrin‐mediated adhesion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Its cell surface availability is further regulated by cytokine‐mediated proteolytic shedding—illustrated by interleukin‐1α–induced extracellular domain release via matrix metalloproteinase‐7 in colon cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " In osteosarcoma, repression of SDC2 via aberrant Wnt/β‐catenin/TCF signaling contributes to decreased apoptosis and the development of chemoresistance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", underscoring its role as a key regulator of cellular fate.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSDC2 also plays important roles in vascular biology and in the pathogenesis of infections. In endothelial cells, growth factor stimulation regulates SDC2 expression to support cell spreading, adhesion, and the formation of capillary‐like structures during angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Notch signaling in vascular smooth muscle cells induces SDC2 expression, which then reinforces proper vessel assembly and differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " In the context of viral infection, RNA interference–mediated depletion of SDC2 impairs herpes simplex virus type 1 entry, highlighting its role in mediating viral attachment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Furthermore, in nasopharyngeal carcinoma the Epstein–Barr virus oncoprotein LMP1 upregulates SDC2 (in concert with synaptotagmin‐like‐4) via NF‐κB signaling to promote extracellular vesicle secretion that enhances tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " Collectively, these findings underscore the multifaceted roles of SDC2 in cell–cell communication, adhesion, and signaling across a spectrum of pathological states."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}, {"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Haein Park, Yeonhee Kim, Yangmi Lim, et al. 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