TAK1与TCF-4在非小细胞肺癌中表达及其相关性的初步研究

doi:10.3969/j.issn.1000-8535.2023.06.003

摘要/Abstract

摘要： 目的探讨非小细胞肺癌（NSCLC）组织中转化生长因子β激活激酶1（TAK-1）与T细胞因子-4（TCF-4）在 mRNA以及蛋白水平的表达情况及其相关性,并分析两者与NSCLC患者临床病理因素的关系。方法收集NSCLC手术标本51例,每例均包含肺癌组织及配对癌旁组织,所有患者的术后诊断均经病理结果证实,通过RT-PCR以及Western blot法检测TAK1、TCF-4在癌组织及配对癌旁组织中的表达情况,并通过SPSS进一步分析两者的相关性及其与临床病理因素的关系。结果 TAK1与TCF-4 mRNA以及蛋白水平在NSCLC患者癌组织中均高表达,其中TAK1蛋白的表达与NSCLC的TNM分期（P=0.022）、淋巴结转移（P=0.014）相关,TCF-4蛋白的表达与NSCLC的TNM分期相关（P=0.045）。TAK1在NSCLC组织中的表达与TCF-4呈正相关（r=0.427,P=0.002）。结论 TAK1 mRNA及蛋白水平在NSCLC组织中均高表达,并与TCF-4呈正相关,TAK1有可能成为NSCLC诊断及预后的一个潜在靶标,并且TAK1与TCF-4的联合应用有可能成为一种更为理想的NSCLC辅助诊断及临床治疗方法。

关键词: 非小细胞肺癌, 转化生长因子激活激酶1, T细胞因子-4, Wnt/β-catenin信号通路

Abstract: Objective To investigate the mRNA and protein expressions of transforming growth factor β-activated kinase 1（TAK1）and T cell factor-4（TCF-4）in non-small cell lung cancer（NSCLC）tissues and their correlation,and to analyze the relationship between TAK1/TCF-4 and clinicopathological factors in NSCLC patients．Methods Cancer tissues and matched adjacent tissues of 51 NSCLC patients in our hospital were collected．The postoperative diagnosis of all patients was confirmed by pathological results．The expression of TAK1 and TCF-4 in cancer tissues and paired adjacent tissues were detected by RT-PCR and Western blot,then SPSS was used to further analyze the correlation between TAK1 and TCF-4 and clinicopathological factors．Results TAK1 and TCF-4 mRNA and protein were highly expressed in NSCLC tissues,and TAK1 protein expression was significantly correlated with TNM stage of NSCLC（P=0.022）and lymph node metastasis（P=0.014）;TCF-4 protein expression was significantly correlated with TNM stage of NSCLC（P=0.045）．TAK1 expression in NSCLC tissues was positively correlated with TCF-4（r=0.427,P=0.002）．Conclusions TAK1 mRNA and protein were highly expressed in NSCLC tissues and positively correlated with TCF-4．TAK1 may become a potential target for the diagnosis and prognosis of NSCLC,and the combined application of TAK1 and TCF-4 may become a more ideal method for the auxiliary diagnosis and clinical treatment of NSCLC．

Key words: NSCLC, TAK1, TCF-4, Wnt/β-catenin signaling pathway

齐泽铖, 李旭, 郭英伟, 徐晓文, 王晓军. TAK1与TCF-4在非小细胞肺癌中表达及其相关性的初步研究[J]. 广州医药, 2023, 54(6): 17-22.

QI Zecheng, LI Xu, GUO Yingwei, XU Xiaowen, WANG Xiaojun. Preliminary study on the expression and correlation of TAK1 and TCF-4 in non-small cell lung cancer[J]. Guangzhou Medical Journal, 2023, 54(6): 17-22.

参考文献

[1] BARTA J A,POWELL C A,WISNIVESKY J P.Global epidemiology of lung cancer[J].Ann Glob Health,2019,85(1):1-8.
[2] OBENAUF A C,ZOU Y,JI A L,et al.Therapy-induced tumour secretomes promote resistance and tumour progression[J].Nature,2015,520(7547):368-372.
[3] UENO K,HIRATA H,HINODA Y,et al.Frizzled homolog proteins,microRNAs and Wnt signaling in cancer[J].Int J Cancer,2013,132(8):1731-1740.
[4] SUN Y B,XU J J.TCF-4 regulated lncRNA-XIST promotes M2 polarization of macrophages and is associated with lung cancer[J].Onco Targets Ther,2019(12): e8055-8062.
[5] GEUKING P,NARASIMAMURTHY R,LEMAITRE B,et al.A non-redundant role for Drosophila Mkk4 and hemipterous/Mkk7 in TAK1-mediated activation of JNK[J].PLoS One,2009,4(11):e7709.
[6] ZHANG N,WEI G,YE J,et al.Effect of curcumin on acute spinal cord injury in mice via inhibition of inflammation and TAK1 pathway[J].Pharmacol Rep,2017,69(5):1001-1006.
[7] 董宁,汤欣,苑晓勇,等.TAK1促进人晶状体上皮细胞上皮间质转化的体外研究[J].中华眼科杂志,2016,52(4):278-284.
[8] YUAN G,ZHAO Y,WU D,et al.MiRNA-20a upregulates TAK1 and increases proliferation in osteosarcoma cells[J].Future Oncol,2018,14(5):461-469.
[9] TOTZKE J,GURBANI D,RAPHEMOT R,et al.Takinib,A Selective TAK1 inhibitor,broadens the therapeutic efficacy of TNF-alpha inhibition for cancer and autoimmune disease[J].Cell Chem Biol,2017,24(8):1029-1039 .
[10] 曹赛,程梅容,刘素娥,等.食管癌组织中TAK1和TAB1的表达及与临床预后的相关性[J].南方医科大学学报,2018,38(7):895-900.
[11] 陈少安,苏增存,陈友根.Wnt/β-catenin-TCF-4通路对肾癌细胞生物学行为的影响及其机制[J].中华医学杂志,2020,100(24):1890-1894.
[12] XIE D,XIE J,WAN Y,et al.Norcantharidin blocks Wnt/beta-catenin signaling via promoter demethylation of WIF-1 in glioma[J].Oncol Rep,2016,35(4):2191-2197.
[13] JIA Z,ZHANG Y,SU Y,et al.CDMP1 overexpression mediates inflammatory cytokineinduced apoptosis via inhibiting the Wnt/betaCatenin pathway in rat dorsal root ganglia neurons[J].Int J Mol Med,2018,42(3):1247-1256.
[14] LI X,WU Y,XIE F,et al.MiR3395p negatively regulates loureirin Ainduced hair follicle stem cell differentiation by targeting DLX5[J].Mol Med Rep,2018,18(2):1279-1286.
[15] LAI K K Y,KAHN M.Pharmacologically targeting the Wnt/beta-Catenin signaling cascade:Avoiding the sword of damocles[J].Handb Exp Pharmacol,2021(269):383-422.
[16] LIU B,GAO T,WU H Y,et al.Erb-B2 receptor tyrosine kinase 2 knockdown inhibits retinoblastoma progression via Wnt/beta-catenin signaling pathway in vitro[J].J Biol Regul Homeost Agents,2021,35(1):209-214.
[17] REN T,FAN X X,WANG M F,et al.MiR20b promotes growth of non-small cell lung cancer through a positive feedback loop of the Wnt/β-catenin signaling pathway[J].Int J Oncol,2020,56(2):470-479.
[18] WARBOYS C M.Mechanoactivation of Wnt/β-catenin pathways in health and disease[J].Emerg Top Life Sci,2018,2(5):701-712.
[19] HWANG J S,YOON C K,HYON J Y,et al.Transcription factor 4 regulates the regeneration of corneal endothelial cells[J].Invest Ophthalmol Vis Sci,2020,61(11):6.
[20] 李勇. 人肺癌组织中NLK与TCF4的表达及临床意义[J].中国民康医学,2016,28(5):79-82.
[21] CHEN X,YE S,XIAO W,et al.ERK1/2 pathway mediates epithelial-mesenchymal transition by cross-interacting with TGFβ/Smad and Jagged/Notch signaling pathways in lens epithelial cells[J].Int J Mol Med,2014,33(6):1664-1670.
[22] OTA S,SHITANI S,SHIMIZU N,et al.NLK positively regulates Wnt/beta-catenin signalling by phosphorylating LEF1 in neural progenitor cells[J].EMBO J,2012,31(8):1904-1915.
[23] ISHITANI T,HIRAO T,SUZUKI M,et al.Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex[J].Nat Cell Biol,2010,12(3):278-285.
[24] TANIGUCHI K,KARIN M.NF-κB,inflammation,immunity and cancer:coming of age[J].Nat Rev Immunol,2018,18(5):309-324.
[25] HUANG Y,JIANG Y,LU W,et al.Nemo-like kinase associated with proliferation and apoptosis by c-Myb degradation in breast cancer[J].PLoS One,2013,8(7):e69148.
[26] 戈锐,周为,燕速,等.结肠腺癌中转化生长因子β激酶1与细胞增殖的关系[J].中国老年学杂志,2016,36(15):3745-3746.
[27] YANG Y,QIU Y,TANG M,et al.Expression and function of transforming growth factor-β-activated protein kinase 1 in gastric cancer[J].Mol Med Rep,2017,16(3):3103-3110.
[28] HUANG F T,PENG J F,CHENG W J,et al.MiR-143 Targeting TAK1 attenuates pancreatic ductal adenocarcinoma progression via MAPK and NF-kappaB pathway in vitro[J].Dig Dis Sci,2017,62(4):944-957.
[29] SHI L,XIN Q,CHAI R,et al.Ectopic expressed miR-203 contributes to chronic obstructive pulmonary disease via targeting TAK1 and PIK3CA[J].Int J Clin Exp Pathol,2015,8(9):10662-10670.
[30] 乔飞. 转化生长因子β激活酶1在食管癌中的表达及其临床意义[J].实用医学杂志,2014,30(19):3084-3087.
[31] YANG Y,XIA F,HERMANCE N,et al.A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase(MAPK)/MAPK-activated protein 2 responses to DNA damage[J].Mol Cell Biol,2011,31(14):2774-2786.