E-Cadherin的表达调控及对细胞增殖的影响
Regulation of E-Cadherin Expression and Effects on Cell Proliferation
DOI: 10.12677/BP.2022.121002, PDF,   
作者: 王冬杨, 吴玉青, 应方莉, 曹诣斌*：浙江师范大学，化学与生命科学学院，浙江 金华
关键词: E-Cadherin；CAT；细胞增殖；转录调控；癌症； E-Cadherin； CAT； Cell Proliferation； Transcriptional Regulation； Cancer
摘要: E-钙粘蛋白(E-cadherin)主要在上皮细胞膜上表达，发挥细胞间粘附作用并抑制入侵，其在细胞增殖的过程中也扮演着重要角色，主要通过Wnt，Hippo信号通路及Rho家族的小GTPases影响上皮细胞的增殖。E-cadherin在细胞膜上的稳定性和准确的功能通过与连环蛋白(catenin, CAT)形成稳定的复合物来实现。E-cadherin功能缺失在癌症细胞中被发现，其表达失调主要发生在表观遗传学水平。E-cadherin表达水平下降与肿瘤的出现、分化、侵入和运动转移等密切相关。本文主要介绍了E-cadherin对细胞增殖的影响，分析了其在肿瘤发生和发展过程中调节细胞增殖、侵袭和细胞内信号传导的一些分子机制。
Abstract: E-cadherin is mainly expressed on epithelial cell membranes, plays an intercellular adhesion and inhibits invasion, which also plays an important role in cell proliferation, mainly affecting epithelial cell proliferation through Wnt, Hippo signaling pathways and small GTPases of the Rho family. The stability and accurate function of E-cadherin at the cell membrane is achieved by forming a stable complex with catenin (CAT). Loss of E-cadherin function has been found in cancer cells, and its dysregulation mainly occurs at the epigenetic level. The decreased expression level of E-cadherin is closely related to the emergence, differentiation, invasion and movement metastasis of tumors. This paper mainly introduces the effect of E-cadherin on cell proliferation and analyzes some of the molecular mechanisms by which it regulates cell proliferation, invasion and intracellular signaling during tumorigenesis and development.
文章引用：王冬杨, 吴玉青, 应方莉, 曹诣斌. E-Cadherin的表达调控及对细胞增殖的影响[J]. 生物过程, 2022, 12(1): 10-19. https://doi.org/10.12677/BP.2022.121002

参考文献

[1] Jeanes, A., Gottardi, C.J. and Yap, A.S. (2008) Cadherins and Cancer: How Does Cadherin Dysfunction Promote Tu-mor Progression? Oncogene, 27, 6920-6929. [Google Scholar] [CrossRef] [PubMed]
[2] Pećina-Šlaus, N. (2003) Tumor Suppressor Gene E-Cadherin and Its Role in Normal and Malignant Cells. Cancer Cell International, 3, Article No. 17. [Google Scholar] [CrossRef] [PubMed]
[3] Peifer, M. and Polakis, P. (2000) Wnt Signaling in Onco-genesis and Embryogenesis—A Look Outside the Nucleus. Science, 287, 1606-1609. [Google Scholar] [CrossRef] [PubMed]
[4] Gumbiner, B.M. (2000) Regulation of Cadherin Adhesive Ac-tivity. The Journal of Cell Biology, 148, 399-404. [Google Scholar] [CrossRef] [PubMed]
[5] 游曼清. 布地奈德对哮喘小鼠气道上皮occludin和E-Cadherin表达的影响[D]: [硕士学位论文]. 泸州: 西南医科大学泸州医学院, 2014.
[6] Nilsson, Gr.E., Dymowska, A. and Stecyk, J.A.W. (2012) New Insights into the Plasticity of Gill Structure. Respiratory Physiology & Neurobiology, 184, 214-222. [Google Scholar] [CrossRef] [PubMed]
[7] Perry, J.K., Lins, R.J., Lobie, P.E. and Mitchell, M.D. (2009) Regulation of Invasive Growth: Similar Epigenetic Mechanisms Underpin Tumour Progression and Implantation in Human Pregnancy. Clinical Science, 118, 451-457. [Google Scholar] [CrossRef] 
[8] Sollid, J., De Angelis, P., Gundersen, K. and Nilsson, G.E. (2003) Hy-poxia Induces Adaptive and Reversible Gross Morphological Changes in Crucian Carp Gills. Journal of Experimental Biology, 206, 3667-3673. [Google Scholar] [CrossRef] [PubMed]
[9] Ireton, R.C., Davis, M.A., van Hengel, J., Mariner, D.J., Barnes, K., Thoreson, M.A., et al. (2002) A Novel Role for P120 Catenin in E-Cadherin Function. The Journal of Cell Biology, 159, 465-476. [Google Scholar] [CrossRef] [PubMed]
[10] Gumbiner, B.M. (1996) Cell Adhesion: The Molecular Basis of Tissue Architecture and Morphogenesis. Cell, 84, 345-357. [Google Scholar] [CrossRef] 
[11] 胡军. E-Cadherin与卵巢癌转移的相关性及机制研究[D]: [博士学位论文]. 大连: 大连医科大学, 2007.
[12] Thiery, J.P., Acloque, H., Huang, R.Y.J. and Nieto, M.A. (2009) Epithelial-Mesenchymal Transitions in Development and Dis-ease. Cell, 139, 871-890. [Google Scholar] [CrossRef] [PubMed]
[13] Lamouille, S., Xu, J. and Derynck, R. (2014) Molecular Mechanisms of Epithelial-Mesenchymal Transition. Nature Reviews Molecular Cell Biology, 15, 178-196. [Google Scholar] [CrossRef] [PubMed]
[14] Stockinger, A., Eger, A., Wolf, J., Beug, H. and Foisner, R. (2001) E-Cadherin Regulates Cell Growth by Modulating Proliferation-Dependent β-Catenin Transcriptional Activity. The Journal of Cell Biology, 154, 1185-1196. [Google Scholar] [CrossRef] [PubMed]
[15] Anastasiadis, P.Z. and Reynolds, A.B. (2000) The P120 Catenin Fam-ily: Complex Roles in Adhesion, Signaling and Cancer. Journal of Cell Science, 113, 1319-1334. [Google Scholar] [CrossRef] [PubMed]
[16] Yap, A.S., Niessen, C.M. and Gumbiner, B.M. (1998) The Juxtamem-brane Region of the Cadherin Cytoplasmic Tail Supports Lateral Clustering, Adhesive Strengthening, and Interaction with P120ctn. The Journal of Cell Biology, 141, 779-789. [Google Scholar] [CrossRef] [PubMed]
[17] Thoreson, M.A., Anastasiadis, P.Z., Daniel, J.M., Ireton, R.C., Wheelock, M.J., Johnson, K.R., et al. (2000) Selective Uncoupling of P120ctn From E-Cadherin Disrupts Strong Adhesion. The Journal of Cell Biology, 148, 189-202. [Google Scholar] [CrossRef] [PubMed]
[18] Soto, E., Yanagisawa, M., Marlow, L.A., Copland, J.A., Perez, E.A., Anastasiadis, P.Z. (2008) P120 Catenin Induces Opposing Effects on Tumor Cell Growth Depending on E-Cadherin Expression. Journal of Cell Biology, 183, 737-749. [Google Scholar] [CrossRef] [PubMed]
[19] Gottardi, C.J., Wong, E. and Gumbiner, B.M. (2001) E-Cadherin Sup-presses Cellular Transformation by Inhibiting β-Catenin Signaling in an Adhesion-Independent Manner. The Journal of Cell Biology, 153, 1049-1060. [Google Scholar] [CrossRef] [PubMed]
[20] Gottardi, C.J. and Gumbiner, B.M. (2001) Adhesion Signaling: How β-Catenin Interacts with Its Partners. Current Biology, 11, R792-R794. [Google Scholar] [CrossRef] 
[21] Kim, N.G., Koh, E., Chen, X. and Gumbiner, B.M. (2011) E-Cadherin Mediates Contact Inhibition of Proliferation through Hippo Signaling-Pathway Components. Proceedings of the National Academy of Sciences of the United States of America, 108, 11930-11935. [Google Scholar] [CrossRef] [PubMed]
[22] Kourtidis, A., Lu, R., Pence, L.J. and Anastasiadis, P.Z. (2017) A Central Role for Cadherin Signaling in Cancer. Experimental Cell Research, 358, 78-85. [Google Scholar] [CrossRef] [PubMed]
[23] Fan, R., Kim, N.G. and Gumbiner, B.M. (2013) Regulation of Hippo Pathway by Mitogenic Growth Factors via Phosphoinositide 3-Kinase and Phosphoinositide-Dependent Kinase-1. Proceedings of the National Academy of Sciences of the United States of America, 110, 2569-2574. [Google Scholar] [CrossRef] [PubMed]
[24] 贾金婧, 张亚帅, 耿文硕, 等. Wnt/β-Catenin信号途径在DDR和氧化应激中的作用[J]. 信阳师范学院学报(自然科学版), 2017, 30(4): 672-675.
[25] 韩丹, 何波, 廖承德. 实验性大鼠恶性胸膜间皮瘤的CT表现与病理对照研究[J]. 临床放射学杂志, 2008, 27(4): 547-550.
[26] Huelsken, J. and Behrens, J. (2002) The Wnt Signalling Pathway. Journal of Cell Science, 115, 3977-3978. [Google Scholar] [CrossRef] [PubMed]
[27] 候壮. 低氧通过MicroRNA-Hippo信号通路促进毛乳头细胞增殖的机制研究[D]: [硕士学位论文]. 呼和浩特: 内蒙古大学, 2020.
[28] 齐海霞, 柴艳芬. Hippo信号通路相关分子与肿瘤发生的研究进展[J]. 医学综述, 2020, 26(4): 683-689.
[29] Zhao, B., Wei, X., Li, W., Udan, R.S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu, J., Li, L., et al. (2007) Inactivation of YAP Oncoprotein by the Hippo Pathway Is Involved in Cell Contact Inhibition and Tissue Growth Control. Genes & Development, 21, 2747-2761. [Google Scholar] [CrossRef] [PubMed]
[30] Rankin, E.B., Rha, J., Selak, M.A., Unger, T.L., Keith, B., Liu, Q. and Haase, V.H. (2009) Hypoxia-Inducible Factor 2 Regulates Hepatic Lipid Metabolism. Molecular and Cellular Biology, 29, 4527-4538. [Google Scholar] [CrossRef] 
[31] Citi, S., Guerrera, D., Spadaro, D. and Shah, J. (2014) Epithelial Junctions and Rho Family GTPases: The Zonular Signalosome. Small GTPases, 5, Article No. e973760. [Google Scholar] [CrossRef] [PubMed]
[32] Asnaghi, L., Vass, W.C., Quadri, R., Day, P.M., Qian, X., Braverman, R., et al. (2010) E-Cadherin Negatively Regulates Neoplastic Growth in Non-Small Cell Lung Cancer: Role of Rho GTPases. Oncogene, 29, 2760-2771. [Google Scholar] [CrossRef] [PubMed]
[33] Malliri, A., Es, S.V., Huveneers, S. and Collard, J.G. (2004) The Rac Exchange Factor Tiam1 Is Required for the Establishment and Maintenance of Cadherin-Based Adhesions. Journal of Biological Chemistry, 279, 30092-30098. [Google Scholar] [CrossRef] 
[34] Katoh, M. (2006) Epithelial-Mesenchymal Transition in Gastric Cancer (Review). International Journal of Oncology, 27, 1677-1683.
[35] Riethmacher, D., Brinkmann, V. and Birch-meier, C. (1995) A Targeted Mutation in the Mouse E-Cadherin Gene Results in Defective Preimplantation Development. Proceedings of the National Academy of Sciences of the United States of America, 92, 855-859. [Google Scholar] [CrossRef] [PubMed]
[36] Fleming, T.P., Javed, Q. and Hay, M. (1992) Epithelial Differentiation and Intercellular Junction Formation in the Mouse Early Embryo. Development, 116, 105-112. [Google Scholar] [CrossRef] 
[37] Fierro-González, J.C., White, M.D., Silva, J.C. and Plachta, N. (2013) Cadherin-Dependent Filopodia Control Preimplantation Embryo Compaction. Nature Cell Biology, 15, 1424-1433. [Google Scholar] [CrossRef] [PubMed]
[38] Bessonnard, S., Mesnard, D. and Constam, D.B. (2015) PC7 and the Related Proteases Furin and Pace4 Regulate E-Cadherin Function during Blastocyst Formation. Journal of Cell Biol-ogy, 210, 1185-1197. [Google Scholar] [CrossRef] [PubMed]
[39] Graff, J.R., Herman, J.G., Lapidus, R.G., Chopra, H., Xu, R., Jarrard, D.F., et al. (1995) E-Cadherin Expression Is Silenced by DNA Hypermethylation in Human Breast and Prostate Carci-nomas. Cancer Research, 55, 5195-5199.
[40] Peinado, H., Olmeda, D. and Cano, A. (2007) Snail, Zeb and BHLH Factors in Tumour Progression: An Alliance Against the Epithelial Phenotype? Nature Reviews Cancer, 7, 415-428. [Google Scholar] [CrossRef] [PubMed]
[41] Hajra, K.M., Chen, D.Y. and Fearon, E.R. (2002) The SLUG Zinc-Finger Protein Represses E-Cadherin in Breast Cancer. Cancer Research, 62, 1613-1618.
[42] Niemhom, S., Kitazawa, S., Kitazawa, R., Maeda, S. and Leopairat, J. (2008) Hypermethylation of Epithelial-Cadherin Gene Promoter Is Associated with Epstein-Barr Virus in Nasopharyngeal Carcinoma. Cancer Detection and Prevention, 32, 127-134. [Google Scholar] [CrossRef] [PubMed]
[43] Park, J. and Jang, K.L. (2014) Hepatitis C Virus Represses E-Cadherin Expression via DNA Methylation to Induce Epithelial to Mesenchymal Transition in Human Hepatocytes. Biochemical and Biophysical Research Communications, 446, 561-567. [Google Scholar] [CrossRef] [PubMed]
[44] Li, L.C., Okino, S.T., Zhao, H., Pookot, D., Place, R.F., Urakami, S., et al. (2006) Small DsRNAs Induce Transcriptional Activation in Human Cells. Proceedings of the National Academy of Sciences of the United States of America, 103, 17337-17342. [Google Scholar] [CrossRef] [PubMed]
[45] Chen, Z., Place, R.F., Jia, Z.J., Pookot, D., Dahiya, R. and Li, L.-C. (2008) Antitumor Effect of DsRNA-Induced P21WAF1/CIP1 Gene Activation in Human Bladder Cancer Cells. Molec-ular Cancer Therapeutics, 7, 698-703. [Google Scholar] [CrossRef] 
[46] Yang, K., Zheng, X.Y., Qin, J., Wang, Y.B., Bai, Y., Mao, Q.Q., et al. (2008) Up-Regulation of p21WAF1/Cip1 by SaRNA Induces G1-Phase Arrest and Apoptosis in T24 Human Bladder Cancer Cells. Cancer Letters, 265, 206-214. [Google Scholar] [CrossRef] [PubMed]
[47] Nickel, A. and Stadler, S.C. (2015) Role of Epigenetic Mecha-nisms in Epithelial-to-Mesenchymal Transition of Breast Cancer Cells. Translational Research, 165, 126-142. [Google Scholar] [CrossRef] [PubMed]
[48] Rothbart, S.B. and Strahl, B.D. (2014) Interpreting the Language of Histone and DNA Modifications. Biochim Biophys Acta, 1839, 627-643. [Google Scholar] [CrossRef] [PubMed]
[49] Tessarz, P. and Kouzarides, T. (2014) Histone Core Modifica-tions Regulating Nucleosome Structure and Dynamics. Nature Reviews Molecular Cell Biology, 15, 703-708. [Google Scholar] [CrossRef] [PubMed]
[50] Dong, C., Wu, Y., Wang, Y., Wang, C., Kang, T., Rychahou, P.G., et al. (2013) Interaction with Suv39H1 Is Critical for Snail-Mediated E-Cadherin Repression in Breast Cancer. Oncogene, 32, 1351-1362. [Google Scholar] [CrossRef] [PubMed]
[51] Fukagawa, A., Ishii, H., Miyazawa, K. and Saitoh, M. (2015) δEF1 Associates with DNMT1 and Maintains DNA Methylation of the E-Cadherin Promoter in Breast Cancer Cells. Cancer Medicine, 4, 125-135. [Google Scholar] [CrossRef] [PubMed]
[52] Vesuna, F., Diest, P.V., Ji, H.C. and Raman, V. (2008) Twist Is a Tran-scriptional Repressor of E-Cadherin Gene Expression in Breast Cancer. Biochemical & Biophysical Research Communi-cations, 367, 235-241. [Google Scholar] [CrossRef] [PubMed]
[53] Grabitz, A.L. and Duncan, M.K. (2012) Focus on Molecules: Smad Interacting Protein 1 (Sip1, ZEB2, ZFHX1B). Experimental Eye Research, 101, 105-106. [Google Scholar] [CrossRef] [PubMed]
[54] Koopmansch, B., Berx, G., Foidart, J.M. and Saitoh, M. (2013) Interplay Between KLF4 and ZEB2/SIP1 in the Regulation of E-Cadherin Expression. Biochemical and Biophysical Re-search Communications, 431, 652-657. [Google Scholar] [CrossRef] [PubMed]
[55] Zhang, Z., Yang, C., Gao, W., Chen, T., Qian, T., Hu, J., et al. (2015) FOXA2 Attenuates the Epithelial to Mesenchymal Transition by Regulating the Transcription of E-Cadherin and ZEB2 in Human Breast Cancer. Cancer Letters, 361, 240-250. [Google Scholar] [CrossRef] [PubMed]
[56] Alotaibi, H., Basilicata, M.F., Shehwana, H., Kosowan, T., Schreck, I., Braeutigam, C., et al. (2015) Enhancer Cooperativity As A Novel Mechanism Underlying the Transcriptional Regulation of E-Cadherin During Mesenchymal to Epithelial Transition. Biochimica et Biophysica Acta (BBA): Gene Regulatory Mechanisms, 1849, 731-742. [Google Scholar] [CrossRef] [PubMed]
[57] Ma, D.N., Chai, Z.T., Zhu, X.D., Zhang, N., Zhan, D.H., Ye, B.G., et al. (2016) MicroRNA-26a Suppresses Epithelial-Mesenchymal Transition in Human Hepatocellular Carcinoma by Repressing Enhancer of Zeste Homolog 2. Journal of Hematology & Oncology, 9, Article No. 1. [Google Scholar] [CrossRef] [PubMed]
[58] Ungewiss, C., Rizvi, Z.H., Roybal, J.D., Peng, D.H., Gold, K.A., Shin, D.H., et al. (2016) The MicroRNA-200/Zeb1 Axis Regulates ECM-Dependent β1-Integrin/FAK Signaling, Cancer Cell Invasion and Metastasis through CRKL. Scientific Reports, 6, Article No.18652. [Google Scholar] [CrossRef] [PubMed]
[59] Song, Y., Li, J., Zhu, Y., Dai, Y., Zeng, T., Liu, L., et al. (2014) Mi-croRNA-9 Promotes Tumor Metastasis via Repressing E-Cadherin in Esophageal Squamous Cell Carcinoma. Oncotar-get, 5, 11669-11680. [Google Scholar] [CrossRef] [PubMed]
[60] Liu, S., Kumar, S.M., Lu, H., Liu, A., Yang, R., Pushparajan, A., et al. (2012) MicroRNA-9 Up-Regulates E-Cadherin through Inhibition of NF-κB1-Snail1 Pathway in Melanoma. The Journal of Pathology, 226, 61-72. [Google Scholar] [CrossRef] [PubMed]