MTA1基因同小细胞肺癌生物学行为的相关性研究
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摘要
目的:通过研究人小细胞肺癌(SCLC)及正常肺组织芯片、肺癌细胞系及肿瘤转移相关蛋白1(MTA1)转基因小鼠,明确SCLC中肿瘤转移相关蛋白1的表达及功能机制。方法:采用免疫组化及免疫印迹分析明确SCLC组织芯片以及MTA1转基因小鼠肺组织MTA1和干细胞转录因子2的表达;检测MTA1-siRNA下调SCLC细胞系中MTA1表达后细胞表型的变化。结果:在SCLC组织芯片及细胞系中MTA1呈高表达状态(P<0.05),其表达量在性别、年龄、肿瘤TNM分期各亚组中无显著差异(P>0.05)。SCLC中下调MTA1表达,肿瘤增殖能力显著降低(P<0.05)。SCLC中下调MTA1表达,肿瘤恶性生物学潜能显著降低。MTA1通过调控干细胞转录因子2参与SCLC的恶性生物学进程。结论:MTA1在SCLC中作为关键调控因子可能涉及肿瘤干细胞调控,并且在SCLC的增殖、凋亡方面具有显著影响。
Objective: The expression and functional mechanism of MTA1 in small cell lung cancer( SCLC) were explained by studying human SCLC and normal lung tissue specimens,lung cancer cell line and MTA1 transgenic mouse. Methods: Immunohistochemistry and western blot were used to clarify the expression level of MTA1 and SOX2 in SCLC tissue specimens and MTA1 transgenic mouse. After knocking down the MTA1 by specific MTA1-siRNA sequence,the biological consequence were evaluated. Results: MTA1 shows high expression in tissue and cell line of small cell lung cancer( P<0.05) and there was no significant difference in the gender,age and TNM staging( P>0.05). Compared with MTA1-NC group,MTA1-siRNA group was significantly reduced in cell proliferation of the lung cancer( P<0.05). MTA1 downregulation suppresses potential of tumor malignant biological potential of the SCLC cell line. MTA1 was involved in the regulation of malignant biological processes in SCLC by regulating SOX2. Conclusion: MTA1 plays a critical role in regulating the malignant behaviors of SCLC and it is closely related to tumor stem cell regulation. It has significant influence on proliferation and apoptosis of SCLC.
Objective: The expression and functional mechanism of MTA1 in small cell lung cancer( SCLC) were explained by studying human SCLC and normal lung tissue specimens,lung cancer cell line and MTA1 transgenic mouse. Methods: Immunohistochemistry and western blot were used to clarify the expression level of MTA1 and SOX2 in SCLC tissue specimens and MTA1 transgenic mouse. After knocking down the MTA1 by specific MTA1-siRNA sequence,the biological consequence were evaluated. Results: MTA1 shows high expression in tissue and cell line of small cell lung cancer( P<0.05) and there was no significant difference in the gender,age and TNM staging( P>0.05). Compared with MTA1-NC group,MTA1-siRNA group was significantly reduced in cell proliferation of the lung cancer( P<0.05). MTA1 downregulation suppresses potential of tumor malignant biological potential of the SCLC cell line. MTA1 was involved in the regulation of malignant biological processes in SCLC by regulating SOX2. Conclusion: MTA1 plays a critical role in regulating the malignant behaviors of SCLC and it is closely related to tumor stem cell regulation. It has significant influence on proliferation and apoptosis of SCLC.
引文
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[31]Deng L,Tang J,Yang H,et al.MTA1 modulated by miR-30e contributes to epithelial-to-mesenchymal transition in hepatocellular carcinoma through an Erb B2-dependent pathway[J].Oncogene,2017,36(28):3976-3985.
[32]Li Y,Lv Z,He G,et al.The SOX17/miR-371-5p/SOX2 axis inhibits EMT,stem cell properties and metastasis in colorectal cancer[J].Oncotarget,2015,6(11):9099-9112.
[33]Radisky DC,La Barge MA.Epithelial-mesenchymal transition and the stem cell phenotype[J].Cell Stem Cell,2008,2(6):511-512.
[2]Soo RA,ECA S,Cummings KM,et al.Scientific advances in thoracic oncology 2016[J].J Thorac Oncol,2017,12(8):1183-1209.
[3]Li DQ,Kumar R.Unravelling the Complexity and Functions of MTA Coregulators in Human Cancer[J].Adv Cancer Res,2015,127:1-47.
[4]Hanahan D,Weinberg RA.Hallmarks of cancer:The next generation[J].Cell,2011,144(5):646-674.
[5]Kumar R,Wang RA,Bagheri-Yarmand R.Emerging roles of MTA family members in human cancers[J].Semin Oncol,2003,30(5Suppl 16):30-37.
[6]Malisetty VL,Penugurti V,Panta P,et al.MTA1 expression in human cancers-Clinical and pharmacological significance[J].Biomed Pharmacother,2017,95:956-964.
[7]Toh Y,Nicolson GL.Properties and clinical relevance of MTA1protein in human cancer[J].Cancer Metastasis Rev,2014,33(4):891-900.
[8]Rudin CM,Durinck S,Stawiski EW,et al.Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer[J].Nat Genet,2012,44(10):1111-1116.
[9]薛洪省,王海娟,刘健,等.MTA1转基因小鼠的构建及鉴定[J].中国比较医学杂志,2013(9):31-35.
[10]Sasaki H,Moriyama S,Nakashima Y,et al.Expression of the MTA1mRNA in advanced lung cancer[J].Lung Cancer,2002,35(2):149-154.
[11]Moon HE,Cheon H,Lee MS.Metastasis-associated protein 1inhibits p53-induced apoptosis[J].Oncol Rep,2007,18(5):1311-1314.
[12]Zhu X,Guo Y,Li X,Ding Y,Chen L.Metastasis-associated protein 1 nuclear expression is associated with tumor progression and clinical outcome in patients with non-small cell lung cancer[J].J Thorac Oncol,2010,5(8):1159-1166.
[13]Li S,Tian H,Yue W,et al.Down-regulation of MTA1 protein leads to the inhibition of migration,invasion,and angiogenesis of non-small-cell lung cancer cell line[J].Acta Biochim Biophys Sin(Shanghai),2013,45(2):115-122.
[14]Ma K,Fan Y,Dong X,et al.MTA1 promotes epithelial to mesenchymal transition and metastasis in non-small-cell lung cancer[J].Oncotarget,2017,8(24):38825-38840.
[15]Toh Y,Nicolson GL.The role of the MTA family and their encoded proteins in human cancers:molecular functions and clinical implications[J].Clin Exp Metastasis,2009,26(3):215-227.
[16]Salot S,Gude R.MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines[J].Eur J Cancer,2013,49(2):492-499.
[17]Lee JY,Park JH,Choi HJ,et al.LSD1 demethylates HIF1αto inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis[J].Oncogene,2017,36(39):5512-5521.
[18]Schmidberger JW,Sharifi Tabar M,Torrado M,et al.The MTA1subunit of the nucleosome remodeling and deacetylase complex can recruit two copies of RBBP4/7[J].Protein Sci,2016,25(8):1472-1482.
[19]Sen N,Gui B,Kumar R.Physiological functions of MTA family of proteins[J].Cancer Metastasis Rev,2014,33(4):869-877.
[20]Xu C,Hua F,Chen Y,et al.MTA1 promotes metastasis of MPM via suppression of E-cadherin[J].J Exp Clin Cancer Res,2015,34:151.
[21]Prieto-García E,Díaz-García CV,García-Ruiz I,et al.Epithelialto-mesenchymal transition in tumor progression[J].Med Oncol,2017,34(7):122.
[22]Foy V,Schenk MW,Baker K,et al.Targeting DNA damage in SCLC[J].Lung Cancer,2017,114:12-22.
[23]Li DQ,Pakala SB,Reddy SD,et al.Bidirectional autoregulatory mechanism of metastasis-associated protein 1-alternative reading frame pathway in oncogenesis[J].Proc Natl Acad Sci USA,2011,108(21):8791-8796.
[24]Feng X,Zhang Q,Xia S,et al.MTA1 overexpression induces cisplatin resistance in nasopharyngeal carcinoma by promoting cancer stem cells properties[J].Mol Cells,2014,37(9):699-704.
[25]Modrek AS,Golub D,Khan T,et al.Low-grade astrocytoma mutations in IDH1,P53,and ATRX cooperate to block differentiation of human neural stem cells via repression of SOX2[J].Cell Rep,2017,21(5):1267-1280.
[26]Cancer Genome Atlas Research Network,Analysis Working Group:Asan University,BC Cancer Agency,Brigham and Women's Hospital,et al.Integrated genomic characterization of oesophageal carcinoma[J].Nature,2017,541(7636):169-175.
[27]Ferone G,Song JY,Sutherland KD,et al.SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin[J].Cancer Cell,2016,30(4):519-532.
[28]Teicher BA.Targets in small cell lung cancer[J].Biochem Pharmacol,2014,87(2):211-219.
[29]Wuebben EL,Rizzino A.The dark side of SOX2:cancer-a comprehensive overview[J].Oncotarget,2017,8(27):44917-44943.
[30]Ozmadenci D,Féraud O,Markossian S,et al.Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance[J].Nat Commun,2015,6:7398.
[31]Deng L,Tang J,Yang H,et al.MTA1 modulated by miR-30e contributes to epithelial-to-mesenchymal transition in hepatocellular carcinoma through an Erb B2-dependent pathway[J].Oncogene,2017,36(28):3976-3985.
[32]Li Y,Lv Z,He G,et al.The SOX17/miR-371-5p/SOX2 axis inhibits EMT,stem cell properties and metastasis in colorectal cancer[J].Oncotarget,2015,6(11):9099-9112.
[33]Radisky DC,La Barge MA.Epithelial-mesenchymal transition and the stem cell phenotype[J].Cell Stem Cell,2008,2(6):511-512.