{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Inter‐α‐trypsin inhibitor heavy chain 5 (ITIH5) is a secreted extracellular matrix (ECM) protein that plays multiple roles in tissue homeostasis and tumor suppression. ITIH5 contributes to ECM stabilization—through its interactions with hyaluronan—and modulates cell–matrix adhesion, which in turn influences cell polarization, migration, and invasion. In several solid tumors, including breast, colon, bladder, lung, pancreatic, gastric, and melanoma, ITIH5 is frequently downregulated, often as a result of promoter hypermethylation. Loss of ITIH5 expression has been associated with increased cell proliferation, enhanced invasive behavior, and unfavorable clinical outcomes, whereas restoration of ITIH5 levels suppresses tumor cell growth and metastasis by reprogramming cellular signaling networks (for example, via modulation of the TGF‐β superfamily and the HA–CD44 axis) and by altering epigenetic marks (1,2,3,7,17)."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In breast cancer, decreased ITIH5 levels correlate with reduced overall survival and recurrence‐free survival. Experimental re‐expression of ITIH5 in aggressive breast cancer cell lines not only diminished proliferation and migration but also triggered an epithelial-like reprogramming that attenuates tumor‐initiating properties (1,7,17). Similar tumor-suppressive functions have been reported in colon cancer, where ITIH5 promoter hypermethylation is linked to its diminished expression and poor prognosis, and in non–small cell lung cancer, with decreased ITIH5 levels marking specific subtypes associated with adverse outcomes (5,6). In bladder cancer, both in urothelial carcinomas and basal‐type bladder cancers, ITIH5 loss—mediated by aberrant methylation—has been correlated with enhanced invasiveness and altered response to chemotherapeutics, indicating its potential as a prognostic biomarker (4,13). Furthermore, studies in pancreatic ductal adenocarcinoma demonstrate that even secretion-deficient ITIH5 can suppress liver metastasis, suggesting that ITIH5 may exert intracellular tumor-suppressive functions as well (10,16). In melanoma, ITIH5 expression is downregulated via mechanisms involving p53 and its low levels are linked to enhanced cell migration and poor clinical outcomes (14). In gastric cancer, reduced ITIH5 expression is associated with higher histological grades and advanced disease stages, further supporting its broad tumor-suppressive role (15).\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond neoplasia, ITIH5 is expressed in normal tissues such as skin and adipose tissue. In skin, ITIH5 produced predominantly by dermal fibroblasts contributes to ECM organization and modulates inflammatory responses, while in adipose tissue its expression correlates with obesity and metabolic parameters (8,12). In addition, alterations in ITIH5 expression have been implicated in non-neoplastic conditions such as Hirschsprung’s disease, where its upregulation is associated with reduced cell migration and proliferation (9). Finally, preclinical models, including canine lymphoma, have validated ITIH5 promoter hypermethylation as a recurring event in tumorigenesis (18).\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish ITIH5 as a multifunctional ECM modulator and a promising candidate tumor suppressor, whose altered expression and epigenetic regulation may serve as valuable biomarkers for early detection, risk stratification, and therapeutic targeting across a variety of cancer types (1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18).\n "}, {"type": "rg", "children": []}]}]}