留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码
x

CUX1及其分子调控机制在人类恶性肿瘤中的研究进展

谢铖 徐安琪 韩磊 崔乃千 宋子彬 陈凯琪 杨荟平 杨宗霖 宋烨

谢铖, 徐安琪, 韩磊, 崔乃千, 宋子彬, 陈凯琪, 杨荟平, 杨宗霖, 宋烨. CUX1及其分子调控机制在人类恶性肿瘤中的研究进展[J]. 分子影像学杂志, 2019, 42(3): 343-348. doi: 10.12122/j.issn.1674-4500.2019.03.16
引用本文: 谢铖, 徐安琪, 韩磊, 崔乃千, 宋子彬, 陈凯琪, 杨荟平, 杨宗霖, 宋烨. CUX1及其分子调控机制在人类恶性肿瘤中的研究进展[J]. 分子影像学杂志, 2019, 42(3): 343-348. doi: 10.12122/j.issn.1674-4500.2019.03.16
Cheng XIE, Anqi XU, Lei HAN, Naiqian CUI, Zibin SONG, Kaiqi CHEN, Huiping YANG, Zonglin YANG, Ye SONG. Advances in the study of CUX1 and its molecular regulatory mechanisms in human malignant tumors[J]. Journal of Molecular Imaging, 2019, 42(3): 343-348. doi: 10.12122/j.issn.1674-4500.2019.03.16
Citation: Cheng XIE, Anqi XU, Lei HAN, Naiqian CUI, Zibin SONG, Kaiqi CHEN, Huiping YANG, Zonglin YANG, Ye SONG. Advances in the study of CUX1 and its molecular regulatory mechanisms in human malignant tumors[J]. Journal of Molecular Imaging, 2019, 42(3): 343-348. doi: 10.12122/j.issn.1674-4500.2019.03.16

CUX1及其分子调控机制在人类恶性肿瘤中的研究进展

doi: 10.12122/j.issn.1674-4500.2019.03.16
基金项目: 国家自然科学基金(81872064)
详细信息
    作者简介:

    谢铖:谢 铖,硕士,E-mail:xuanqi_799@163.com

    通讯作者:

    宋 烨,博士,副教授,副主任医师,硕士生导师,E-mail:songye@smu.edu.cn

Advances in the study of CUX1 and its molecular regulatory mechanisms in human malignant tumors

  • 摘要: 同源框CUT样蛋白1(CUX1),又称CDP(CCAAT位移蛋白),CUT或CUTL1,是DNA结合蛋白同源域家族的成员。CUX1基因在转录和翻译过程中形成不同长度的蛋白亚型,包括P200、P110和P75。除髓系白血病外,CUX1蛋白被发现在乳腺癌、肺癌、胰腺癌、胶质瘤、胰腺神经内分泌肿瘤等多种癌组织中过表达,在癌旁组织中不表达或低表达,且表达量与肿瘤恶性程度和病人预后相关。因此,CUX1可作为多种恶性肿瘤诊断的新型分子标志物及治疗靶点。在肿瘤中的长期研究中逐渐明晰CUX1的作用机制,解释其癌基因和抑癌基因的矛盾。在机制研究中发现,全长CUX1蛋白可以促进DNA碱基修复,与肿瘤耐药性相关;CUX1短亚型可以通过介导PI3K/AKT,Wnt/β-catenin,TGF-β等信号通路调控肿瘤的增殖、迁移和侵袭过程。本文重点介绍CUX1与肿瘤的相关性及其调控机制的研究进展。

     

  • [1] Bray F, Ferlay J, Soerjomataram I, et al. Global Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. doi: 10.3322/caac.v68.6
    [2] 陈万青, 孙可欣, 郑荣寿, 等. 2014年中国分地区恶性肿瘤发病和死亡分析[J]. 中国肿瘤, 2018, 27(1): 1-14. doi: 10.3969/j.issn.1674-4136.2018.01.001
    [3] Kedinger V, Nepveu A. The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion[J]. Cell Adh Migr, 2010, 4(3): 348-52. doi: 10.4161/cam.4.3.11407
    [4] Cubelos B, Sebastián-Serrano A, Beccari L, et al. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex[J]. Neuron, 2010, 66(4): 523-35. doi: 10.1016/j.neuron.2010.04.038
    [5] Ellis T, Gambardella L, Horcher M, et al. The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle[J]. Genes Dev, 2001, 15(17): 2307-19. doi: 10.1101/gad.200101
    [6] Rong Zeng W, Soucie E, Sung Moon N, et al. Exon/intron structure and alternative transcripts of the CUTL1 gene[J]. Gene, 2000, 241(1): 75-85. doi: 10.1016/S0378-1119(99)00465-5
    [7] Ramdzan ZM, Nepveu A. CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers[J]. Nat Rev Cancer, 2014, 14(10): 673-82. doi: 10.1038/nrc3805
    [8] Kaur S, Ramdzan ZM, Guiot MC, et al. CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide[J]. Neuro Oncol, 2018, 20(4): 484-93. doi: 10.1093/neuonc/nox178
    [9] Truscott M, Raynal L, Wang Y, et al. The N-terminal region of the CCAAT displacement protein (CDP)/Cux transcription factor functions as an autoinhibitory domain that modulates DNA binding[J]. J Biol Chem, 2004, 279(48): 49787-94. doi: 10.1074/jbc.M409484200
    [10] Arthur RK, An N, Khan S, et al. The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters[J]. Nucleic Acids Res, 2017, 45(11): 6350-61. doi: 10.1093/nar/gkx218
    [11] Sharma M, Fopma A, Brantley JG, et al. Coexpression of Cux-1 and notch signaling pathway components during kidney development[J]. Dev Dyn, 2004, 231(4): 828-38. doi: 10.1002/dvdy.v231:4
    [12] Sharma M, Brantley JG, Vassmer D, et al. The homeodomain protein Cux1 interacts with Grg4 to repress p27 kip1 expression during kidney development[J]. Gene, 2009, 439(1/2): 87-94.
    [13] Sinclair AM, Lee JA, Goldstein A, et al. Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice[J]. Blood, 2001, 98(13): 3658-67. doi: 10.1182/blood.V98.13.3658
    [14] Tufarelli C, Fujiwara Y, Zappulla DC, et al. Hair defects and pup loss in mice with targeted deletion of the first cut repeat domain of the Cux/CDP homeoprotein gene[J]. Dev Biol, 1998, 200(1): 69-81. doi: 10.1006/dbio.1998.8950
    [15] Ramdzan ZM, Vadnais C, Pal R, et al. RAS transformation requires CUX1-dependent repair of oxidative DNA damage[J]. PLoS Biol, 2014, 12(3): e1001807. doi: 10.1371/journal.pbio.1001807
    [16] Truscott M, Denault JB, Goulet B, et al. Carboxyl-terminal proteolytic processing of CUX1 by a caspase enables transcriptional activation in proliferating cells[J]. J Biol Chem, 2007, 282(41): 30216-26. doi: 10.1074/jbc.M702328200
    [17] Sansregret L, Goulet B, Harada R, et al. The p110 isoform of the CDP/Cux transcription factor accelerates entry into S phase[J]. Mol Cell Biol, 2006, 26(6): 2441-55. doi: 10.1128/MCB.26.6.2441-2455.2006
    [18] Kedinger V, Sansregret L, Harada R, et al. p110 CUX1 homeodomain protein stimulates cell migration and invasion in part through a regulatory cascade culminating in the repression of e-cadherin and occludin[J]. J Biol Chem, 2009, 284(40): 27701-11. doi: 10.1074/jbc.M109.031849
    [19] Vadnais C, Shooshtarizadeh P, Rajadurai CV, et al. Autocrine activation of the Wnt/β-Catenin pathway by CUX1 and GLIS1 in breast cancers[J]. Biol Open, 2014, 3(10): 937-46. doi: 10.1242/bio.20148193
    [20] Goulet B, Baruch A, Moon NS, et al. A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor[J]. Mol Cell, 2004, 14(2): 207-19. doi: 10.1016/S1097-2765(04)00209-6
    [21] Moon NS, Premdas P, Truscott M, et al. S phase-specific proteolytic cleavage is required to activate stable DNA binding by the CDP/Cut homeodomain protein[J]. Mol Cell Biol, 2001, 21(18): 6332-45. doi: 10.1128/MCB.21.18.6332-6345.2001
    [22] Goulet B, Watson P, Poirier M, et al. Characterization of a tissue-specific CDP/Cux isoform, p75, activated in breast tumor cells[J]. Cancer Res, 2002, 62(22): 6625-33.
    [23] Cadieux C, Kedinger V, Yao L, et al. Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types[J]. Cancer Res, 2009, 69(18): 7188-97. doi: 10.1158/0008-5472.CAN-08-4899
    [24] Wang J, Wang Y, Sun D, et al. CUTL1 induces epithelial-mesenchymal transition in non-small cell lung Cancer[J]. Oncol Rep, 2017, 37(5): 3068-74. doi: 10.3892/or.2017.5571
    [25] Michl P, Ramjaun AR, Pardo OE, et al. CUTL1 is a target of TGF(beta) signaling that enhances Cancer cell motility and invasiveness[J]. Cancer Cell, 2005, 7(6): 521-32. doi: 10.1016/j.ccr.2005.05.018
    [26] Ripka S, König A, Buchholz M, et al. WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic Cancer[J]. Carcinogenesis, 2007, 28(6): 1178-87. doi: 10.1093/carcin/bgl255
    [27] Krug S, Kühnemuth B, Griesmann H, et al. CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms[J]. Endocr Relat Cancer, 2014, 21(6): 879-90. doi: 10.1530/ERC-14-0152
    [28] Burton LJ, Dougan J, Jones J, et al. Targeting the nuclear cathepsin L CCAAT displacement protein/cut homeobox transcription Factor-Epithelial mesenchymal transition pathway in prostate and breast Cancer cells with the Z-FY-CHO inhibitor[J]. Mol Cell Biol, 2017, 37(5): e00297-16.
    [29] Luna-Fineman S, Shannon KM, Atwater SK, et al. Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients[J]. Blood, 1999, 93(2): 459-66.
    [30] Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes[J]. J Clin Oncol, 2011, 29(5): 504-15. doi: 10.1200/JCO.2010.31.1175
    [31] Patnaik MM, Tefferi A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia[J]. Blood Cancer J, 2016, 6(2): e393. doi: 10.1038/bcj.2016.5
    [32] Mcnerney ME, Brown CD, Wang X, et al. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia[J]. Blood, 2013, 121(6): 975-83. doi: 10.1182/blood-2012-04-426965
    [33] Wong CC, Martincorena I, Rust AG, et al. Inactivating CUX1 mutations promote tumorigenesis[J]. Nat Genet, 2014, 46(1): 33-8. doi: 10.1038/ng.2846
    [34] An N, Khan S, Imgruet MK, et al. Gene dosage effect of CUX1 in a murine model disrupts HSC homeostasis and controls the severity and mortality of MDS[J]. Blood, 2018, 131(24): 2682-97. doi: 10.1182/blood-2017-10-810028
    [35] Cadieux C, Fournier S, Peterson AC, et al. Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia[J]. Cancer Res, 2006, 66(19): 9492-501. doi: 10.1158/0008-5472.CAN-05-4230
    [36] Zeng WR, Watson P, Lin J, et al. Refined mapping of the region of loss of heterozygosity on the long arm of chromosome 7 in human breast Cancer defines the location of a second tumor suppressor gene at 7q22 in the region of the CUTL1 gene[J]. Oncogene, 1999, 18(11): 2015-21. doi: 10.1038/sj.onc.1202519
    [37] Wilson BJ, Harada R, Leduy L, et al. CUX1 transcription factor is a downstream effector of the proteinase-activated receptor 2(PAR2) J][J]. J Biol Chem, 2009, 284(1): 36-45. doi: 10.1074/jbc.M803808200
    [38] Burton LJ, Henderson V, Liburd L, et al. Snail transcription factor NLS and importin β1 regulate the subcellular localization of Cathepsin L and Cux1[J]. Biochem Biophys Res Commun, 2017, 491(1): 59-64. doi: 10.1016/j.bbrc.2017.07.039
    [39] Chen J, Zhou Z, Yao Y, et al. Dipalmitoylphosphatidic acid inhibits breast Cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway[J]. J Cell Mol Med, 2018, 22(10): 4760-70. doi: 10.1111/jcmm.13727
    [40] Wang L, Zhao Y, Xiong Y, et al. K-ras mutation promotes ionizing radiation-induced invasion and migration of lung Cancer in part via the Cathepsin L/CUX1 pathway[J]. Exp Cell Res, 2018, 362(2): 424-35. doi: 10.1016/j.yexcr.2017.12.006
    [41] Ripka S, Neesse A, Riedel J, et al. CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic Cancer[J]. Gut, 2010, 59(8): 1101-10. doi: 10.1136/gut.2009.189720
    [42] Ripka S, Riedel J, Neesse A, et al. Glutamate receptor GRIA3--target of CUX1 and mediator of tumor progression in pancreatic Cancer[J]. Neoplasia, 2010, 12(8): 659-67. doi: 10.1593/neo.10486
    [43] Griesmann H, Ripka S, Pralle M, et al. WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic Cancer[J]. Neoplasia, 2013, 15(1): 11-22. doi: 10.1593/neo.121312
    [44] Kühnemuth B, Mühlberg L, Schipper M, et al. CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling[J]. Oncogene, 2015, 34(2): 177-87. doi: 10.1038/onc.2013.530
    [45] Fei Y, Xiong Y, Shen X, et al. Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3β/CUX1 pathway[J]. Cell Signal, 2018, 44(4): 62-71.
    [46] Fei Y, Xiong Y, Shen X, et al. Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3β/CUX1 pathway[J]. Cell Signal, 2018, 44(4): 62-71.
    [47] 樊 星. 转录因子CUTL1在恶性黑素瘤发生发展中的作用及机制研究[D]. 上海: 第二军医大学, 2011.
    [48] 王红红. 转录因子CUTL1在胃癌多药耐药中的作用及机制研究[D]. 西安: 第四军医大学, 2012.
  • 加载中
计量
  • 文章访问数:  1777
  • HTML全文浏览量:  974
  • PDF下载量:  29
  • 被引次数: 0
出版历程
  • 收稿日期:  2019-06-13
  • 刊出日期:  2019-07-01

目录

    /

    返回文章
    返回