{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nReprimo (RPRM) is a p53-inducible gene that plays a pivotal role in enforcing a G2/M cell cycle arrest in response to DNA damage and cellular stress. Under such conditions, RPRM acts as a cell cycle inhibitor, and its induction is associated with the maintenance of genomic integrity. Multiple studies indicate that RPRM’s tumor suppressor function is compromised in several cancers, where its down‐regulation—often through epigenetic silencing such as promoter methylation—has been proposed as a non‐invasive biomarker for early cancer detection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic investigations have revealed that RPRM expression is subject to complex regulatory inputs. For instance, estrogen receptor alpha (ERα) in conjunction with coregulators such as HDAC7 and FoxA1 mediates rapid repression of RPRM, demonstrating a hormone-sensitive axis of regulation. Moreover, experimental re-expression of RPRM in cancer cell models—including those derived from pituitary tumors, gastric cancers, and pediatric acute myeloid leukemia—results in significant reductions in cell proliferation, induction of cell death, and impaired anchorage-independent growth. These studies underscore that aberrant promoter methylation and other epigenetic modifications not only silence RPRM expression but also contribute to enhanced tumor invasiveness and progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional insights from comparative studies, including investigations using the zebrafish model, highlight that RPRM and its homolog RPRML exhibit conserved expression patterns in the digestive tract, vasculature, and central nervous system—supporting their fundamental role in cellular homeostasis. In breast cancer, for example, elevated RPRM promoter methylation in ERα-positive tumors further implicates hormonal regulation in its silencing. Noncoding RNAs such as LINC00467 have also been implicated in promoting DNMT1-mediated methylation of the RPRM promoter, thereby diminishing its tumor-suppressive effects in gastric cancers and other neoplastic lesions such as intraductal papillary mucinous neoplasms. Collectively, these findings demonstrate that loss of RPRM function—whether by transcriptional repression, epigenetic modification, or posttranscriptional degradation—is a common event in tumorigenesis and highlights its potential utility as both a diagnostic marker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Norihiro Sato, Noriyoshi Fukushima, Hiroyuki Matsubayashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant methylation of Reprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cncr.21977"}], "href": "https://doi.org/10.1002/cncr.21977"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16752411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16752411"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "William D Beasley, John Beynon, Gareth J S Jenkins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reprimo 824 G>C and p53R2 4696 C>G single nucleotide polymorphisms and colorectal cancer: a case-control disease association study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Colorectal Dis (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00384-007-0435-3"}], "href": "https://doi.org/10.1007/s00384-007-0435-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18197409"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18197409"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Carolina Bernal, Francisco Aguayo, Cynthia Villarroel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reprimo as a potential biomarker for early detection in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-07-4522"}], "href": "https://doi.org/10.1158/1078-0432.CCR-07-4522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18829507"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18829507"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Simeen Malik, Shiming Jiang, Jason P Garee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00907-09"}], "href": "https://doi.org/10.1128/MCB.00907-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19917725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19917725"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jun Luo, Youqing Zhu, Guifang Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diagn Cytopathol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dc.21461"}], "href": "https://doi.org/10.1002/dc.21461"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20949468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20949468"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mei Xu, Aaron J Knox, Katherine A Michaelis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reprimo (RPRM) is a novel tumor suppressor in pituitary tumors and regulates survival, proliferation, and tumorigenicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2011-2021"}], "href": "https://doi.org/10.1210/en.2011-2021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22562171"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22562171"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kok-Siong Yeo, Taznim Begam Mohd Mohidin, Ching-Ching Ng "}, {"type": "b", "children": [{"type": "t", "text": "Epstein-Barr virus-encoded latent membrane protein-1 upregulates 14-3-3σ and Reprimo to confer G(2)/M phase cell cycle arrest."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "C R Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.crvi.2012.11.002"}], "href": "https://doi.org/10.1016/j.crvi.2012.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23312294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23312294"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Akira Ooki, Keishi Yamashita, Kensei Yamaguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA damage-inducible gene, reprimo functions as a tumor suppressor and is suppressed by promoter methylation in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-13-0091"}], "href": "https://doi.org/10.1158/1541-7786.MCR-13-0091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23982217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23982217"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yan-Fang Tao, Zhi-Heng Li, Na-Na Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "tp53-dependent G2 arrest mediator candidate gene, Reprimo, is down-regulated by promoter hypermethylation in pediatric acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Lymphoma (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/10428194.2015.1011157"}], "href": "https://doi.org/10.3109/10428194.2015.1011157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25629980"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25629980"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kathleen Saavedra, José Valbuena, Wilda Olivares, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of Expression of Reprimo, a p53-induced Cell Cycle Arrest Gene, Correlates with Invasive Stage of Tumor Progression and p73 Expression in Gastric Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0125834"}], "href": "https://doi.org/10.1371/journal.pone.0125834"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25954972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25954972"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Lianhua Liu, Xiaofeng Yang "}, {"type": "b", "children": [{"type": "t", "text": "Implication of Reprimo and hMLH1 gene methylation in early diagnosis of gastric carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26823831"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26823831"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Hanze Wang, Yansong Zheng, Junzhong Lai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylation-Sensitive Melt Curve Analysis of the Reprimo Gene Methylation in Gastric Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0168635"}], "href": "https://doi.org/10.1371/journal.pone.0168635"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27992600"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27992600"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Ricardo J Figueroa, Gonzalo Carrasco-Avino, Ignacio A Wichmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reprimo tissue-specific expression pattern is conserved between zebrafish and human."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0178274"}], "href": "https://doi.org/10.1371/journal.pone.0178274"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28562620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28562620"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Kurt Buchegger, Ismael Riquelme, Tamara Viscarra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reprimo, a Potential p53-Dependent Tumor Suppressor Gene, Is Frequently Hypermethylated in Estrogen Receptor α-Positive Breast Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms18081525"}], "href": "https://doi.org/10.3390/ijms18081525"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28809778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28809778"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Tetsuya Nakazato, Yutaka Suzuki, Ryota Tanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of Reprimo Down-regulation on Malignant Transformation of Intraductal Papillary Mucinous Neoplasm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pancreas (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MPA.0000000000001002"}], "href": "https://doi.org/10.1097/MPA.0000000000001002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29401170"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29401170"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Julio D Amigo, Juan C Opazo, Roddy Jorquera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Reprimo Gene Family: A Novel Gene Lineage in Gastric Cancer with Tumor Suppressive Properties."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms19071862"}], "href": "https://doi.org/10.3390/ijms19071862"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29941787"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29941787"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yuanyuan Wu, Juan Du "}, {"type": "b", "children": [{"type": "t", "text": "Downregulated Reprimo by LINC00467 participates in the growth and metastasis of gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2022.2063662"}], "href": "https://doi.org/10.1080/21655979.2022.2063662"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35549646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35549646"}]}]}]}