纤维连接蛋白1在胃癌中的表达及临床意义
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摘要
目的纤维连接蛋白1(FN1)参与癌症发生发展的机制尚不清楚。文章旨在研究FN1在胃癌组织中的表达和临床病理意义,并探讨FN1作用机制。方法采用人类肿瘤相关基因表达汇编(GEO)数据库和癌症基因组图谱(TCGA)数据库,下载GSE54129、GSE29272和TCGA数据分析胃癌与癌旁组织FN1的表达。根据TCGA表达谱数据及FN1表达分为:低表达(<-0.475)、中表达(-0.475～1.036)、高表达(>1.036)。分析FN1在胃癌组织中的表达和临床病理关系;应用TCGA数据和Kaplan Meier在线分析FN1的表达水平与胃癌患者的预后关系;TCGA数据采用基因集富集分析(GSEA)方法预测FN1的相关通路。结果 FN1低、中、高表达的中位生存时间分别为63.5、55.7和39.4个月,低表达和高表达者中位生存时间差异具有统计学意义(P<0.01)。Kaplan-Meier Plotter在线数据集分析结果显示,FN1高表达者中位生存时间短于低表达者(P<0.01),即FN1表达越高,预后越差。FN1的表达是胃癌患者的独立预后因素(HR=0.480,95%CI:0.336～0.686)。FN1高表达样本富集到KRAS(FDR=0.0025)、P53(FDR=0.0052)、TGF-β(FDR=0.0052)、细胞黏附(FDR=0.0)、细胞外基质(FDR=0.0043)、骨架蛋白调控(FDR=0.0057)等基因集(P均<0.01)。结论 FN1的高表达是胃癌预后不良的因素,可作为预测胃癌转移和预后的有效生物标志物。FN1高表达导致KRAS、P53、TGF-β、ECM、细胞黏附和细胞骨架蛋白调节通路异常可能是其作用机制。
Objective Fibronectin 1(FN1)is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to investigate the expression and clinicopathological significance of FN1 in gastric cancer and to predict the possible mechanism of FN1.Methods GEO data and TCGA data were downloaded. FN1 expression in gastric cancer and adjacent tissues was analyzed by GSE54129 data,and then verified by GSE29272 and TCGA data. According to the expression profile data and FN1 expression,mRNA expression value was divided into low expression(<-0.475),and medium expression(-0.475～1.036),high expression(>1.036). FN1 expression in gastric cancer and clinicopathological relationship were analyzed. TCGA data and Kaplan Meier were used to analyze the relationship between the expression level of FN1 and the prognosis of gastric cancer patients;while gene concentration analysis(GSEA)was used to predict the related path of FN1.Results TCGA data showed the medium survival time of low,medium,high FN1 expression was respectively 63.5,55.7,39.4 months,and the difference between low expression and high expression in survival time was of statistical significance. Kaplan Meier Plotter online data analysis showed the medium survival time of FN1 high expression was shorter than that of low expression(P<0.01),which meant the higher the FN1 expression was,the worse the prognosis was. FN1 expression is an independent prognostic factor(HR=0.480,95% CI:0.336～0.686). High expression of FN1 samples enriched gene sets such as KRAS(FDR=0.052),P53(FDR=0.052),TGF-β(FDR=0.052),cell adhesion(FDR=0.0),extracellular matrix(FDR=0.043)and cytoskeletal protein regulation(FDR=0.052).Conclusion The high expression of FN1 is a poor prognostic factor for gastric cancer and can be used as an effective biomarker for predicting the metastasis and prognosis of gastric cancer. High expression of FN1 leads to abnormalities in KRAS,P53,TGF-β,ECM,cell adhesion and cytoskeletal protein regulatory pathways.
Objective Fibronectin 1(FN1)is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to investigate the expression and clinicopathological significance of FN1 in gastric cancer and to predict the possible mechanism of FN1.Methods GEO data and TCGA data were downloaded. FN1 expression in gastric cancer and adjacent tissues was analyzed by GSE54129 data,and then verified by GSE29272 and TCGA data. According to the expression profile data and FN1 expression,mRNA expression value was divided into low expression(<-0.475),and medium expression(-0.475～1.036),high expression(>1.036). FN1 expression in gastric cancer and clinicopathological relationship were analyzed. TCGA data and Kaplan Meier were used to analyze the relationship between the expression level of FN1 and the prognosis of gastric cancer patients;while gene concentration analysis(GSEA)was used to predict the related path of FN1.Results TCGA data showed the medium survival time of low,medium,high FN1 expression was respectively 63.5,55.7,39.4 months,and the difference between low expression and high expression in survival time was of statistical significance. Kaplan Meier Plotter online data analysis showed the medium survival time of FN1 high expression was shorter than that of low expression(P<0.01),which meant the higher the FN1 expression was,the worse the prognosis was. FN1 expression is an independent prognostic factor(HR=0.480,95% CI:0.336～0.686). High expression of FN1 samples enriched gene sets such as KRAS(FDR=0.052),P53(FDR=0.052),TGF-β(FDR=0.052),cell adhesion(FDR=0.0),extracellular matrix(FDR=0.043)and cytoskeletal protein regulation(FDR=0.052).Conclusion The high expression of FN1 is a poor prognostic factor for gastric cancer and can be used as an effective biomarker for predicting the metastasis and prognosis of gastric cancer. High expression of FN1 leads to abnormalities in KRAS,P53,TGF-β,ECM,cell adhesion and cytoskeletal protein regulatory pathways.
引文
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[13]Cai X,Liu C,Zhang TN,et al.Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation,migration,and invasion[J].J cellular biochem,2018,119(6):4717-4728.
[14]Boguslawska J,Kedzierska H,Poplawski P,et al.Expression of genes involved in cellular adhesion and extracellular matrix remodeling correlates with poor survival of patients with renal cancer[J].J urol,2016,195(6):1892-1902.
[15]Morita Y,Hata K,Nakanishi M,et al.Cellular fibronectin 1promotes VEGF-C expression,lymphangiogenesis and lymph node metastasis associated with human oral squamous cell carcinoma[J].Clin exp metastasis,2015,32(7):739-753.
[16]Sengupta S,Nandi S,Hindi ES,et al.Short hairpin RNA-mediated fibronectin knockdown delays tumor growth in a mouse glioma model[J].Neoplasia,2010,12(10):837-847.
[17]Ahmed N,Stenvers K.Getting to know ovarian cancer ascites:opportunities for targeted therapy-based translational research[J].Front oncol,2013,3:256.
[18]Xing H,Weng D,Chen G,et al.Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells[J].Cancer lett,2008,261(1):108-119.
[19]Shibata K,Kikkawa F,Nawa A,et al.Both focal adhesion kinase and c-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells[J].Cancer res,1998,58(5):900-903.
[20]赵文甲,刘维,吴沅皞.干燥综合征相关差异表达基因的筛选[J].医学研究生学报,2018,31(9):916-920.
[21]刘健,李青,彭万达,等.CX3CL1 mRNA表达水平对肺腺癌及鳞状细胞癌患者的预后价值分析[J].医学研究生学报,2018,31(12):1296-1300.
[22]Xu T,Xia R,Liu X,et al.Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression[J].J hematol oncol,2014,7(1):63.
[2]张国华,徐颖,邹晨,等.长链非编码RNA DGCR5在胃癌中的表达及临床意义[J].医学研究生学报,2018,31(1):33-38.
[3]Chen W,Zheng R,Baade P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[4]Ioachim E,Charchanti A,Briasoulis E,et al.Immunohistochemical expression of extracellular matrix components tenascin,fibronectin,collagen type IV and laminin in breast cancer:their prognostic value and role in tumour invasion and progression[J].Eur J Cancer,2002,38(18):2362-2370.
[5]Foroni C,Broggini M,Generali D,et al.Epithelial-mesenchymal transition and breast cancer:Role,molecular mechanisms and clinical impact[J].Cancer treat rev,2012,38(6):689-697.
[6]Han SW,Khuri FR,Roman J.Fibronectin stimulates nonsmall cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways[J].Cancer res,2006,66(1):315-323.
[7]Korah R,Boots M,Wieder R.Integrinα5β1 Promotes Survival of Growth-Arrested Breast Cancer Cells:An in Vitro Paradigm for Breast Cancer Dormancy in Bone Marrow[J].Cancer Res,2004,64(13):4514-4522.
[8]Steffens S,Schrader A J,Vetter G,et al.Fibronectin 1 protein expression in clear cell renal cell carcinoma[J].Oncol lett,2012,3(4):787-790.
[9]Ritzenthaler JD,Han SW,Roman J.Stimulation of lung carcinoma cell growth by fibronectin-integrin signalling[J].Mol bioSyst,2008,4(12):1160-1169.
[10]Wang F,Song G,Liu M,et al.miRNA-1 targets fibronectin1and suppresses the migration and invasion of the HEp2 laryngeal squamous carcinoma cell line[J].FEBS lett,2011,585(20):3263-3269.
[11]Chen SH,Lin CY,Lee LT,et al.Up-regulation of fibronectin and tissue transglutaminase promotes cell invasion involving increased association with integrin and MMP expression in A431cells[J].Anticancer res,2010,30(10):4177-4186.
[12]Thiery JP,Sleeman J P.Complex networks orchestrate epithelial-mesenchymal transitions[J].Nat Rev Mol Cell Biol,2006,7(2):131-142.
[13]Cai X,Liu C,Zhang TN,et al.Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation,migration,and invasion[J].J cellular biochem,2018,119(6):4717-4728.
[14]Boguslawska J,Kedzierska H,Poplawski P,et al.Expression of genes involved in cellular adhesion and extracellular matrix remodeling correlates with poor survival of patients with renal cancer[J].J urol,2016,195(6):1892-1902.
[15]Morita Y,Hata K,Nakanishi M,et al.Cellular fibronectin 1promotes VEGF-C expression,lymphangiogenesis and lymph node metastasis associated with human oral squamous cell carcinoma[J].Clin exp metastasis,2015,32(7):739-753.
[16]Sengupta S,Nandi S,Hindi ES,et al.Short hairpin RNA-mediated fibronectin knockdown delays tumor growth in a mouse glioma model[J].Neoplasia,2010,12(10):837-847.
[17]Ahmed N,Stenvers K.Getting to know ovarian cancer ascites:opportunities for targeted therapy-based translational research[J].Front oncol,2013,3:256.
[18]Xing H,Weng D,Chen G,et al.Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells[J].Cancer lett,2008,261(1):108-119.
[19]Shibata K,Kikkawa F,Nawa A,et al.Both focal adhesion kinase and c-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells[J].Cancer res,1998,58(5):900-903.
[20]赵文甲,刘维,吴沅皞.干燥综合征相关差异表达基因的筛选[J].医学研究生学报,2018,31(9):916-920.
[21]刘健,李青,彭万达,等.CX3CL1 mRNA表达水平对肺腺癌及鳞状细胞癌患者的预后价值分析[J].医学研究生学报,2018,31(12):1296-1300.
[22]Xu T,Xia R,Liu X,et al.Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression[J].J hematol oncol,2014,7(1):63.