{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CMTM3 is an evolutionarily conserved transmembrane protein that plays multifaceted roles in both oncogenesis and normal physiology. In several epithelial malignancies—including gastric, prostate, clear cell renal, head and neck, hepatocellular carcinomas, and chordomas—CMTM3 functions as a tumor suppressor. Its re‐expression has been shown to inhibit tumor cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), while its epigenetic silencing via promoter hypermethylation is frequently associated with aggressive disease and poorer clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": " Mechanistic studies indicate that CMTM3 facilitates the degradation of the epidermal growth factor receptor (EGFR) by interacting with the early endosomal machinery (via Rab5 activation), thereby suppressing downstream signaling through the STAT3/Twist1 pathway and reducing MMP2 expression. In endothelial cells, CMTM3 additionally contributes to angiogenesis by regulating the turnover of VE‐cadherin at adherens junctions, a process critical for vascular sprouting."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its tumor‐suppressive functions, CMTM3 is expressed in immune and reproductive tissues. It is highly transcribed in the testis, leukocytes, and spleen and can repress androgen receptor transactivation and prostate‐specific antigen (PSA) expression, suggesting a role in male reproductive physiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Moreover, studies in goat hair follicle stem cells have revealed that modulation of CMTM3 levels affects cell cycle progression and apoptosis, thereby influencing the formation of high‐quality brush hair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings position CMTM3 as a critical regulator of key signaling pathways that govern tumorigenicity, angiogenesis, and tissue differentiation. Its frequent epigenetic inactivation in various cancers, along with its roles in receptor trafficking and cell–cell adhesion, underscore its potential as a promising biomarker and therapeutic target in diverse clinical contexts.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wanqiong Yuan, Baocai Liu, Xiaolin Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CMTM3 decreases EGFR expression and EGF-mediated tumorigenicity by promoting Rab5 activity in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2016.11.015"}], "href": "https://doi.org/10.1016/j.canlet.2016.11.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27867015"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27867015"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wanqiong Yuan, Ting Li, Xiaoning Mo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of CMTM3 promotes metastasis of gastric cancer via the STAT3/Twist1/EMT signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.8789"}], "href": "https://doi.org/10.18632/oncotarget.8789"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27121055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27121055"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yu Su, Yi Lin, Lianhai Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CMTM3 inhibits cell migration and invasion and correlates with favorable prognosis in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.12304"}], "href": "https://doi.org/10.1111/cas.12304"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24131472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24131472"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mingdong Lu, Yingpeng Huang, Weijian Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-135b-5p promotes gastric cancer progression by targeting CMTM3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2017.4222"}], "href": "https://doi.org/10.3892/ijo.2017.4222"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29345297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29345297"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Zhisen Shen, Xiaoying Chen, Qun Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated methylation of CMTM3 promoter in the male laryngeal squamous cell carcinoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Biochem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clinbiochem.2016.08.002"}], "href": "https://doi.org/10.1016/j.clinbiochem.2016.08.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27521994"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27521994"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Wujun Li, Shaobo Zhang "}, {"type": "b", "children": [{"type": "t", "text": "CKLF-Like MARVEL Transmembrane Domain-Containing Member 3 (CMTM3) Inhibits the Proliferation and Tumorigenisis in Hepatocellular Carcinoma Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504016X14732523471442"}], "href": "https://doi.org/10.3727/096504016X14732523471442"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27629543"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27629543"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Heyu Zhang, Jianyun Zhang, Xu Nan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CMTM3 inhibits cell growth and migration and predicts favorable survival in oral squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-015-3504-1"}], "href": "https://doi.org/10.1007/s13277-015-3504-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25946973"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25946973"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zhong Lin Yu, Zheng Ming Zhu "}, {"type": "b", "children": [{"type": "t", "text": "Comprehensive analysis of N6-methyladenosine -related long non-coding RNAs and immune cell infiltration in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2021.1923381"}], "href": "https://doi.org/10.1080/21655979.2021.1923381"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33955330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33955330"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ihsan Chrifi, Laura Louzao-Martinez, Maarten Brandt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CMTM3 (CKLF-Like Marvel Transmembrane Domain 3) Mediates Angiogenesis by Regulating Cell Surface Availability of VE-Cadherin in Endothelial Adherens Junctions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.116.308792"}], "href": "https://doi.org/10.1161/ATVBAHA.116.308792"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28428220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28428220"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ji Zhong, Yu Wang, Xiaoyan Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization and expression profile of CMTM3/CKLFSF3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biochem Mol Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5483/bmbrep.2006.39.5.537"}], "href": "https://doi.org/10.5483/bmbrep.2006.39.5.537"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17002874"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17002874"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yu Wang, Ting Li, Xiaoyan Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CMTM3 can affect the transcription activity of androgen receptor and inhibit the expression level of PSA in LNCaP cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2008.03.143"}], "href": "https://doi.org/10.1016/j.bbrc.2008.03.143"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18402773"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18402773"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Shoubin Li, Peng Gao, Xingliang Dai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New prognostic biomarker "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "CMTM3"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " in low grade glioma and its immune infiltration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Transl Med (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.21037/atm-22-526"}], "href": "https://doi.org/10.21037/atm-22-526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35280380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35280380"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Qiang Wang, Liuming Zhang, Dejun Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CMTM3 overexpression promotes cell apoptosis while DHT promotes cell proliferation in hair follicle stem cells (HFSCs)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2020.12.029"}], "href": "https://doi.org/10.1016/j.ygeno.2020.12.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33358944"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33358944"}]}]}]}