Advances in research of E26 transforming specific homologous factor EHF/ESE3 in tumors
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摘要: E26转化特异性同源因子[ETS（E26 transformation-specific）homologous factor，EHF]属于ETS家族转录因子。EHF广泛存在于细胞核内，能够单独或与其他效应分子形成转录复合物，增强或抑制下游靶基因的转录，参与细胞增殖、分化、凋亡、衰老等过程。EHF在前列腺癌、胰腺癌、食管癌及结肠癌中发挥抑癌作用，在口腔鳞癌、胃癌、卵巢癌、甲状腺癌、头颈部鳞癌及乳腺癌中发挥促癌作用。在免疫微环境方面，EHF可影响肿瘤细胞相关免疫因子的表达进而对微环境中调节性T细胞、骨髓来源的抑制细胞以及树突细胞产生调控作用。近年来，EHF在肿瘤以及免疫微环境中的病理生理功能越来越受到关注，本文就EHF结构、功能及作用机制的相关研究进展做一综述，以期为肿瘤治疗提供新的靶标及分子预测标记。
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关键词:
- E26转化特异性同源因子 /
- 肿瘤 /
- 研究进展
Abstract: EHF [ETS (E26 transformation-specific) homologous factor/epithelium-specific ETS factor family member 3, ESE3] is a member of the ETS superfamily. EHF is mainly located in cell nuclei. It is a transcription factor that can directly bind to the promoter region of genes or form a transcription complex with other molecules to enhance or inhibit the transcription of downstream target genes. EHF is involved in multiple cell processes including cell proliferation, differentiation, apoptosis, and senescence. EHF plays a role as a tumor suppressor in cancers such as prostate, pancreatic, esophageal, and colon cancers. However, it acts as an oncogene in oral squamous cell carcinoma, gastric cancer, ovarian cancer, thyroid cancer, head and neck squamous cell carcinoma, and breast cancer. In the immune microenvironment, EHF can regulate the expression of some important immune factors and further affect the infiltration and function of the regulatory T cells, myeloid derived suppressor cells, and dendritic cells. In recent years, the pathophysiological function of EHF in tumors and their immune microenvironment has attracted increasing attention. This article reviews the research progress concerning the structure, function, and mechanism of EHF for the identification of new targets and molecular predictive markers for tumor therapy.-
Key words:
- ETS transforming specific homologous factor /
- tumor /
- research progress
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表 1 EHF在不同肿瘤中的作用及靶点
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[1] Luk IY, Reehorst CM, Mariadason JM. ELF3, ELF5, EHF and SPDEF transcription factors in tissue homeostasis and cancer[J]. Molecules, 2018, 23(9):E2191. doi: 10.3390/molecules23092191 [2] Kameyama N, Kobayashi K, Shimizu S, et al. Involvement of ESE-3, epithelial-specific ETS factor family member 3, in transactivation of the ABCB1 gene via pregnane X receptor in intestine-derived LS180 cells but not in liver-derived HepG2 cells[J]. Drug Metab Pharmacokinet, 2016, 31(5):340-348. doi: 10.1016/j.dmpk.2016.05.004 [3] Hollenhorst PC, Ferris MW, Hull MA, et al. Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells[J]. Genes Dev, 2011, 25(20):2147-2157. doi: 10.1101/gad.17546311 [4] Madison BJ, Clark KA, Bhachech N, et al. Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN- FOS at composite DNA sites[J]. 2018, 293(48): 18624-18635. http://www.jbc.org/content/293/48/18624.short [5] Madison BJ, Clark KA, Bhachech N, et al. Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites[J]. J Biol Chem, 2018, 293(48):18624-18635. doi: 10.1074/jbc.RA118.003352 [6] Albino D, Longoni N, Curti L, et al. ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features[J]. Cancer Res, 2012, 72(11): 2889-2900. doi: 10.1158/0008-5472.CAN-12-0212 [7] Albino D, Civenni G, Rossi S, et al. The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment[J]. Oncotarget, 2016, 7(47):76756-76768. https://www.ncbi.nlm.nih.gov/pubmed/27732936 [8] Dallavalle C, Albino D, Civenni G, et al. MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression[J]. J Clin Invest, 2016, 126(12):4585-4602. doi: 10.1172/JCI86505 [9] Cangemi R, Mensah A, Albertini V, et al. Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer[J]. Oncogene, 2008, 27(20):2877-2885. doi: 10.1038/sj.onc.1210953 [10] Longoni N, Kunderfranco P, Pellini S, et al. Aberrant expression of the neuronal- specific protein DCDC2 promotes malignant phenotypes and is associated with prostate cancer progression[J]. Oncogene, 2013, 32(18):2315-2324. doi: 10.1038/onc.2012.245 [11] Kunderfranco P, Mello-Grand M, Cangemi R, et al. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer[J]. PLoS One, 2010, 5(5):e10547. doi: 10.1371/journal.pone.0010547 [12] Zhao T, Jiang W, Wang X, et al. ESE3 inhibits pancreatic cancer metastasis by upregulating E-cadherin[J]. Cancer Res, 2017, 77(4):874- 885. doi: 10.1158/0008-5472.CAN-16-2170 [13] 肖笛, 赵天锁, 俞鸣.乏氧和低糖条件下低表达ESE3促进胰腺癌细胞的侵袭[J].天津医药, 2019, 47(3):225-229. http://d.old.wanfangdata.com.cn/Periodical/tjyy201903001 [14] Wang L, Xing J, Cheng R, et al. Abnormal localization and tumor suppressor function of epithelial tissue- specific transcription factor ESE3 in esophageal squamous cell carcinoma[J]. PLoS One, 2015, 10(5):e0126319. doi: 10.1371/journal.pone.0126319 [15] Lim JH, Cho JY, Park YB, et al. ESE-3 transcription factor is involved in the expression of death receptor (DR)- 5 through putative Ets sites[J]. Biochem Biophys Res Commun, 2006, 350(3):736-741. doi: 10.1016/j.bbrc.2006.09.102 [16] 聂娜, 宋杨, 杨静, 等.Ese-3在结肠癌组织中的表达及意义[J].现代肿瘤医学, 2015, 23(11):1544-1546. doi: 10.3969/j.issn.1672-4992.2015.11.20 [17] 聂娜.Ese-3基因表达对结肠癌细胞HCT15增殖的影响[D].西安: 第四军医大学, 2015. http://cdmd.cnki.com.cn/Article/CDMD-90032-1015961137.htm [18] Taniue K, Oda T, Hayashi T, et al. A member of the ETS family, EHF, and the ATPase RUVBL1 inhibit p53-mediated apoptosis[J]. EMBO Rep, 2011, 12(7):682-689. doi: 10.1038/embor.2011.81 [19] Huang WC, Jang TH, Tung SL, et al. A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing beta5-integrin/c-met signaling pathway[J]. J Exp Clin Cancer Res, 2019, 38(1):89. doi: 10.1186/s13046-019-1091-5 [20] Shi J, Qu Y, Li X, et al. Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer[J]. Cell Death Dis, 2016, 7(10):e2442. doi: 10.1038/cddis.2016.346 [21] 徐勇超, 唐礼恭, 李星, 等.下调E26转化特异性转录因子的表达水平抑制胃癌细胞生长的研究[J].中华实验外科杂志, 2018, 35(11): 2072-2074. doi: 10.3760/cma.j.issn.1001-9030.2018.11.030 [22] Gong YC, Ren GL, Liu B, et al. miR206 inhibits cancer initiating cells by targeting EHF in gastric cancer[J]. Oncol Rep, 2017, 38(3):1688-1694. doi: 10.3892/or.2017.5794 [23] Cheng Z, Guo J, Chen L, et al. Knockdown of EHF inhibited the proliferation, invasion and tumorigenesis of ovarian cancer cells[J]. Mol Carcinog, 2016, 55(6):1048-1059. doi: 10.1002/mc.22349 [24] Brenne K, Nymoen DA, Hetland TE, et al. Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival[J]. Hum Pathol, 2012, 43(4):496-505. doi: 10.1016/j.humpath.2011.05.023 [25] Lv Y, Sui F, Ma J, et al. Increased expression of EHF contributes to thyroid tumorigenesis through transcriptionally regulating HER2 and HER3[J]. Oncotarget, 2016, 7(36):57978-57990. https://www.ncbi.nlm.nih.gov/pubmed/27517321 [26] Novoplansky O, Fury M, Prasad M, et al. MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer[J]. Int J Cancer, 2019, 145(3):748-762. doi: 10.1002/ijc.32170 [27] Galang CK, Muller WJ, Foos G, et al. Changes in the expression of many Ets family transcription factors and of potential target genes in normal mammary tissue and tumors[J]. J Biol Chem, 2004, 279 (12):11281-11292. doi: 10.1074/jbc.M311887200 [28] He J, Pan Y, Hu J, et al. Profile of Ets gene expression in human breast carcinoma[J]. Cancer Biol Ther, 2007, 6(1):76-82. doi: 10.4161/cbt.6.1.3551 [29] Liu J, Jiang W, Zhao K, et al. Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma[J]. J Exp Med, 2019, 216(3):656-673. doi: 10.1084/jem.20180749 [30] 王翔, 金雪荣, 宋扬, 等.结肠癌细胞中Ese-3对树突状细胞分化成熟的影响[J].现代肿瘤医学, 2018, 26(4):506-510. doi: 10.3969/j.issn.1672-4992.2018.04.005 [31] Fossum SL, Mutolo MJ, Tugores A, et al. Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease[J]. J Biol Chem, 2017, 292(26):10938-10949. doi: 10.1074/jbc.M117.775304 [32] Wu J, Duan R, Cao H, et al. Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation[J]. Cell Res, 2008, 18(6):649-663. doi: 10.1038/cr.2008.57 [33] Fossum SL, Mutolo MJ, Yang R, et al. Ets homologous factor regulates pathways controlling response to injury in airway epithelial cells[J]. Nucleic Acids Res, 2014, 42(22):13588-13598. doi: 10.1093/nar/gku1146 [34] Asai T, Morrison SL. The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model[J]. J Biol Chem, 2013, 288(15):10395-103405. doi: 10.1074/jbc.M112.437475 [35] Yamazaki S, Nakano N, Honjo A, et al. The transcription factor ehf is involved in tgf-beta-induced suppression of fcepsilonri and c-kit expression and fcepsilonri-mediated activation in mast cells[J]. J Immunol, 2015, 195(7):3427-3435. doi: 10.4049/jimmunol.1402856 [36] Sprater F, Hovden AO, Appel S. Expression of ESE-3 isoforms in immunogenic and tolerogenic human monocyte- derived dendritic cells[J]. PLoS One, 2012, 7(11):e49577. doi: 10.1371/journal.pone.0049577 [37] Sprater F, Azeem W, Appel S. Activation of peroxisome proliferatoractivated receptor gamma leads to upregulation of ESE-3 expression in human monocyte-derived dendritic cells[J]. Scand J Immunol, 2014, 79(1):20-26. doi: 10.1111/sji.12126 -
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