{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRARRES1, also known as TIG1, encodes a retinoic acid–responsive transmembrane protein that is frequently inactivated in cancer. Multiple studies have demonstrated that its expression is lost through promoter hypermethylation in various tumor types—including gastric, esophageal, and hepatocellular carcinomas—suggesting that normal TIG1/RARRES1 function helps to restrain malignant transformation. In particular, one study identified TIG1 as a retinoid‐inducible, putative tumor suppressor whose silencing is common in human cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn breast and placental malignancies, however, RARRES1 function appears more context dependent. In inflammatory breast cancer, high tumoral TIG1/RARRES1 expression correlates with shorter patient survival by stabilizing the receptor tyrosine kinase Axl and activating downstream NF‑κB and matrix metalloproteinase‐9 signaling. In contrast, maintained expression in basal‐like triple‐negative breast cancers—resulting from promoter hypomethylation—and its ability to restrict cell proliferation indicate a classical tumor suppressor role. Similar epigenetic regulation was observed in nasopharyngeal carcinoma and in placental tissues, where loss of RARRES1 parallels the invasive behavior of choriocarcinomas."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRARRES1 further modulates intracellular signaling by affecting cytoskeletal dynamics and cellular metabolism. It functions as a transmembrane carboxypeptidase inhibitor by interacting with AGBL2, thereby regulating the tubulin tyrosination cycle, and it suppresses glucose uptake by targeting DNAJC8. In addition, by modulating the Fbxw7/cyclin E1 axis via inhibition of PLK2 activity, RARRES1 can restrain cell cycle progression and proliferation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn renal and fibrotic settings, RARRES1 appears to play a dual role. Experimental models of organ fibrosis have uncovered early induction of RARRES1 expression—hinting at a role in fibrogenesis—while in the kidney, overexpression and subsequent proteolytic cleavage of RARRES1 in podocytes activate p53‐dependent apoptotic pathways, contributing to glomerulosclerosis. In addition, secreted RARRES1 has been found in the conditioned media of neurofibroma‐derived Schwann cells, suggesting that its extracellular activity may also influence disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRARRES1’s tumor‐suppressive impact extends to several other malignancies. In prostate cancer, genotype‐associated hypermethylation of RARRES1 correlates with adverse clinical features. In colorectal and testicular cancers, TIG1/RARRES1 interacts with proteins such as TMEM192, cathepsin V, and SPINK2 to inhibit epithelial–mesenchymal transition and reduce invasiveness. Moreover, in osteosarcoma and melanoma, restoration of RARRES1 expression suppresses cell growth, migration, and invasion—effects that have been linked to modulation of mTOR signaling and other downstream pathways. Collectively, these findings underscore a multifaceted role for RARRES1/TIG1 as a mediator of differentiation, cell cycle control, and metabolic reprogramming, with therapeutic implications across a spectrum of cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emile M Youssef, Xu-qi Chen, Eisaku Higuchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypermethylation and silencing of the putative tumor suppressor Tazarotene-induced gene 1 in human cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.can-03-0164"}], "href": "https://doi.org/10.1158/0008-5472.can-03-0164"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15059893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15059893"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hirozumi Mizuiri, Kazuhiro Yoshida, Tetsuya Toge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA methylation of genes linked to retinoid signaling in squamous cell carcinoma of the esophagus: DNA methylation of CRBP1 and TIG1 is associated with tumor stage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1349-7006.2005.00082.x"}], "href": "https://doi.org/10.1111/j.1349-7006.2005.00082.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16128742"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16128742"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Min Soo Son, Min-Ju Kang, Ho Chul Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and mutation analysis of TIG1 (tazarotene-induced gene 1) in human gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504009789745584"}], "href": "https://doi.org/10.3727/096504009789745584"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19806788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19806788"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiaoping Wang, Hitomi Saso, Takayuki Iwamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-13-0967"}], "href": "https://doi.org/10.1158/0008-5472.CAN-13-0967"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24014597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24014597"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Krysta M Coyle, J Patrick Murphy, Dejan Vidovic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9858"}], "href": "https://doi.org/10.18632/oncotarget.9858"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27286452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27286452"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Wai Kei Kwok, Jesse Chung Sean Pang, Kwok Wai Lo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of the RARRES1 gene in nasopharyngeal carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Genet Cytogenet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cancergencyto.2009.06.005"}], "href": "https://doi.org/10.1016/j.cancergencyto.2009.06.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19737656"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19737656"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "H Huebner, R Strick, D L Wachter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-017-0634-x"}], "href": "https://doi.org/10.1186/s13046-017-0634-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29169400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29169400"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ziad J Sahab, Michael D Hall, You Me Sung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the α-tubulin tyrosination cycle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-10-2294"}], "href": "https://doi.org/10.1158/0008-5472.CAN-10-2294"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21303978"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21303978"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Chun-Hua Wang, Rong-Yaun Shyu, Chang-Chieh Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tazarotene-Induced Gene 1 Interacts with DNAJC8 and Regulates Glycolysis in Cervical Cancer Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cells (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14348/molcells.2018.2347"}], "href": "https://doi.org/10.14348/molcells.2018.2347"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29902837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29902837"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Chun-Hua Wang, Tzung-Ju Lu, Lu-Kai Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tazarotene-induced gene 1 interacts with Polo-like kinase 2 and inhibits cell proliferation in HCT116 colorectal cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biol Int (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbin.11681"}], "href": "https://doi.org/10.1002/cbin.11681"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34314079"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34314079"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Andreas Teufel, Diana Becker, Susanne N Weber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of RARRES1 as a core regulator in liver fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Med (Berl) (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00109-012-0919-7"}], "href": "https://doi.org/10.1007/s00109-012-0919-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22669512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22669512"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Hui-Ling Chen, Haeri Seol, Kristy Jean Brown, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Secretome survey of human plexiform neurofibroma derived Schwann Cells reveals a secreted form of the RARRES1 protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms13079380"}], "href": "https://doi.org/10.3390/ijms13079380"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22942771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22942771"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xi-Hua Chen, Wen-Guang Wu, Jian Ding "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant TIG1 methylation associated with its decreased expression and clinicopathological significance in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-013-1129-9"}], "href": "https://doi.org/10.1007/s13277-013-1129-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24006221"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24006221"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ye Feng, Zeguo Sun, Jia Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.kint.2024.04.011"}], "href": "https://doi.org/10.1016/j.kint.2024.04.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38697478"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38697478"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Michael Kloth, Wolfgang Goering, Teodora Ribarska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.27628"}], "href": "https://doi.org/10.1002/ijc.27628"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22573467"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22573467"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Rong-Yaun Shyu, Chun-Hua Wang, Chang-Chieh Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tazarotene-Induced Gene 1 Enhanced Cervical Cell Autophagy through Transmembrane Protein 192."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cells (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14348/molcells.2016.0161"}], "href": "https://doi.org/10.14348/molcells.2016.0161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27989102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27989102"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Chun-Hua Wang, Lu-Kai Wang, Chang-Chieh Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cathepsin V Mediates the Tazarotene-induced Gene 1-induced Reduction in Invasion in Colorectal Cancer Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Biophys (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12013-020-00940-3"}], "href": "https://doi.org/10.1007/s12013-020-00940-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32918681"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32918681"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Rong-Yaun Shyu, Chun-Hua Wang, Chang-Chieh Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tazarotene-Induced Gene 1 (TIG1) Interacts with Serine Protease Inhibitor Kazal-Type 2 (SPINK2) to Inhibit Cellular Invasion of Testicular Carcinoma Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2019/6171065"}], "href": "https://doi.org/10.1155/2019/6171065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31886233"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31886233"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Lina Ma, Yongsheng Ma, Ailing Lian "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of miR-769-5p/Retinoic Acid Receptor Responder 1 Axis in the Progression of Osteosarcoma: Characterization of Potential Therapeutic Targets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacology (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000520803"}], "href": "https://doi.org/10.1159/000520803"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35152215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35152215"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Chun-Hua Wang, Lu-Kai Wang, Chang-Chieh Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIG1 Inhibits the mTOR Signaling Pathway in Malignant Melanoma Through the VAC14 Protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.21873/anticanres.16430"}], "href": "https://doi.org/10.21873/anticanres.16430"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37247911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37247911"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Meng Liu, Ruimin Bai, Guanfei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RARRES1 identified by comprehensive bioinformatic analysis and experimental validation as a promising biomarker in Skin Cutaneous Melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-024-65032-1"}], "href": "https://doi.org/10.1038/s41598-024-65032-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38898266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38898266"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Chun-Hua Wang, I-Shiang Tzeng, Lu-Kai Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tazarotene-induced Gene 1 Induces Melanoma Cell Death by Triggering Endoplasmic Reticulum Stress Response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (Landmark Ed) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.31083/j.fbl2906233"}], "href": "https://doi.org/10.31083/j.fbl2906233"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38940043"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38940043"}]}]}]}