{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hyaluronan and proteoglycan link protein 3 (HAPLN3) belongs to a family of ECM‐associated link proteins that facilitate the binding and stabilization of proteoglycans on hyaluronan. Several independent studies have shown that HAPLN3 plays dual roles. On one hand, its normal function appears to be structural—reinforcing ECM organization in diverse tissues such as the vascular wall, where it is co‐localized with versican and up‐regulated by growth factors like PDGF, and even in biomineralization processes, as suggested by its identification among proteoglycan core proteins modulating eggshell calcification (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " On the other hand, multiple cancer studies have highlighted aberrant epigenetic regulation and altered expression of HAPLN3. In prostate cancer, for example, hypermethylation of the HAPLN3 promoter is part of diagnostic and prognostic methylation signatures that distinguish malignant from benign tissue with high sensitivity and specificity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " Similarly, increased HAPLN3 gene expression in breast cancer has been correlated with HER2 receptor levels"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and inclusion of HAPLN3 in a four‐gene signature has been shown to predict prognosis and therapeutic response in melanoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Additional studies report modulation of HAPLN3 expression by immune stimuli—in particular, its up‐regulation as an interferon‑β response gene in B cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "—and differential methylation in other clinical contexts such as gestational diabetes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "and in analyses of fetal and perinatal death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Moreover, preliminary expression profiling in triple‑negative breast cancer suggests that HAPLN3 may be among a subset of over‑expressed genes contributing to tumor development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, HAPLN3 is implicated both in maintaining extracellular matrix integrity and in the pathogenesis of various diseases—most notably in multiple cancers where its altered methylation and expression profiles provide promising avenues for its use as a diagnostic and prognostic biomarker. This multifunctional role underscores its potential as a target for future therapeutic strategies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroko Ogawa, Toshitaka Oohashi, Masataka Sata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lp3/Hapln3, a novel link protein that co-localizes with versican and is coordinately up-regulated by platelet-derived growth factor in arterial smooth muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2004.07.001"}], "href": "https://doi.org/10.1016/j.matbio.2004.07.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15464361"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15464361"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Pauline Marie, Valérie Labas, Aurélien Brionne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Quantitative proteomics provides new insights into chicken eggshell matrix protein functions during the primary events of mineralisation and the active calcification phase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteomics (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jprot.2015.05.034"}], "href": "https://doi.org/10.1016/j.jprot.2015.05.034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26049031"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26049031"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Christa Haldrup, Kamilla Mundbjerg, Else Marie Vestergaard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2012.47.1847"}], "href": "https://doi.org/10.1200/JCO.2012.47.1847"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23918943"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23918943"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Christa Haldrup, Anne L Pedersen, Nadia Øgaard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/1878-0261.12183"}], "href": "https://doi.org/10.1002/1878-0261.12183"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29465788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29465788"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Palak G Patel, Thomas Wessel, Atsunari Kawashima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A three-gene DNA methylation biomarker accurately classifies early stage prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prostate (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pros.23895"}], "href": "https://doi.org/10.1002/pros.23895"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31433512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31433512"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shou-Jen Kuo, Su-Yu Chien, Che Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Significant elevation of CLDN16 and HAPLN3 gene expression in human breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or_00000918"}], "href": "https://doi.org/10.3892/or_00000918"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20664984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20664984"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Haiya Bai, Youliang Wang, Huimin Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Development of a Four-mRNA Expression-Based Prognostic Signature for Cutaneous Melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fgene.2021.680617"}], "href": "https://doi.org/10.3389/fgene.2021.680617"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34335689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34335689"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Rana Khsheibun, Tamar Paperna, Anat Volkowich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene expression profiling of the response to interferon beta in Epstein-Barr-transformed and primary B cells of patients with multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0102331"}], "href": "https://doi.org/10.1371/journal.pone.0102331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25025430"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25025430"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Daniel A Enquobahrie, Amy Moore, Seid Muhie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Early Pregnancy Maternal Blood DNA Methylation in Repeat Pregnancies and Change in Gestational Diabetes Mellitus Status—A Pilot Study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Sci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1933719115570903"}], "href": "https://doi.org/10.1177/1933719115570903"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25676578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25676578"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jane E Armes, Mark Williams, Gareth Price, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Dev Pathol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1093526617715528"}], "href": "https://doi.org/10.1177/1093526617715528"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28641477"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28641477"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Sandra Karina Santuario-Facio, Servando Cardona-Huerta, Yadira Xitlalli Perez-Paramo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2119/molmed.2016.00257"}], "href": "https://doi.org/10.2119/molmed.2016.00257"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28474731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28474731"}]}]}]}