基于TCGA数据库探讨fibronectin 1在甲状腺癌中的表达及临床意义
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摘要
目的:研究fibronectin 1(FN1)在甲状腺癌的表达情况,探讨FN1与临床参数的关系,预测其在肿瘤发生发展中的可能机制。方法:从癌症基因组图谱(TCGA)数据库下载甲状腺癌中FN1的RNA SEq V2资料和临床信息,分别采用SPSS进行数据统计比较甲状腺癌组织和非肿瘤甲状腺组织中FN1的表达,利用linkedomics在线分析系统总结fibronectin 1与临床病理参数的关系,使用Kaplan-Meier Plotter进行无复发生存期比较,通过linkedomics在线系统中的基因富集分析(GSEA)分析预测可能相关的信号通路。结果:FN1在甲状腺癌组织中的mRNA表达显著增多(16. 663 0±0. 378 6 vs 12. 182 4±0. 139 6,P <0. 000 1; 16. 724 4±0. 124 1 vs 12. 182 4±0. 139 6,P <0. 000 1),在乳头状甲状腺癌中的表达偏高(P=0. 197×10-33),随T分期增加表达逐渐升高(P=3. 321×10-8),在淋巴结转移N1中表达显著增高(P=9. 963×10-16),随病理分级增加表达升高(P=2. 780×10-9)和随残余增多时表达量升高(P=7. 481×10-3)。高表达FN1的患者无复发生存期显著短于低表达患者(HR高表达=2; PHR=0. 026 <0. 05)。FN1高表达样本富集了NF-κB通路,肿瘤坏死因子(TNF)信号通路中激活的PI3K/AKT途径,细胞黏附分子(cell adhesion molecules)中激活的Claudin-1-Notch pathway-EMT途径和甲状腺激素合成(thyroid hormone synthesis)中抑制的PAX8/PPARγ途径等基因集。验证实验结果发现甲状腺癌的肿瘤基质中FN1表达、mRNA转录水平和蛋白表达显著升高。结论:甲状腺癌中FN1上调表达,符合肿瘤研究的相关通路,可以作为预测淋巴结转移和判断预后的重要因子。
Objective: To investigate the value of fibronectin 1 in thyroid cancer,the relation between fibronectin 1 and clinic-pathological situation and to prognosticate the mechanisms involved. Methods: The RNA SEq V2 data and clinical information of fibronectin 1 in thyroid cancer from the cancer Genome Atlas( TCGA) was downloaded. The comparisons of fibronectin 1 expression between carcinoma samples and non-cancer tissue were performed statistically by the software SPSS. The relationship between fibronectin 1 and clinic-pathological factors were analyzed by the online tool linkedomics. The gap of the disease free survival was compared by the Kaplan-Meier Plotter. Gene set enrichment analysis( GSEA) was used to predict the gene sets modulated by fibronectin 1. Results: The mRNA expression of fibronectin 1 was significantly high in thyroid cancer[16. 663 0 ± 0. 378 6 vs 12. 182 4 ± 0. 139 6( P <0. 000 1). 16. 724 4 ± 0. 124 1 vs 12. 182 4 ± 0. 139 6( P < 0. 000 1) ]. High level of fibronectin 1 was showed in papillary thyroid cancer( P = 0. 197 × 10-33),advanced T stage( P = 3. 321 × 10-8),advanced N1 stage( P = 9. 963 ×10-16) advanced c TNM stage( P = 2. 780 × 10-9),more residual cancer( P = 7. 481 × 10-3) and associated with poor disease free survival( HRhigh expression= 2. PHR= 0. 026 < 0. 05). Fibronectin 1 could regulate the gene sets such as NF-κB pathway,PI3 K/AKT pathway in TNF signaling,Claudin-1-Notch pathway-EMT in cell adhesion molecules and PAX8/PPARγ in thyroid hormone synthesis. The proofed experiments showed the mRNA transcription levels and protein expressions increased significantly,which illustrated in the thyroid cancer matrix. Conclusion: Upregulation of fibronectin 1 was found in thyroid cancer,in accordance with the pathways involved and played a potential prognostic marker.
Objective: To investigate the value of fibronectin 1 in thyroid cancer,the relation between fibronectin 1 and clinic-pathological situation and to prognosticate the mechanisms involved. Methods: The RNA SEq V2 data and clinical information of fibronectin 1 in thyroid cancer from the cancer Genome Atlas( TCGA) was downloaded. The comparisons of fibronectin 1 expression between carcinoma samples and non-cancer tissue were performed statistically by the software SPSS. The relationship between fibronectin 1 and clinic-pathological factors were analyzed by the online tool linkedomics. The gap of the disease free survival was compared by the Kaplan-Meier Plotter. Gene set enrichment analysis( GSEA) was used to predict the gene sets modulated by fibronectin 1. Results: The mRNA expression of fibronectin 1 was significantly high in thyroid cancer[16. 663 0 ± 0. 378 6 vs 12. 182 4 ± 0. 139 6( P <0. 000 1). 16. 724 4 ± 0. 124 1 vs 12. 182 4 ± 0. 139 6( P < 0. 000 1) ]. High level of fibronectin 1 was showed in papillary thyroid cancer( P = 0. 197 × 10-33),advanced T stage( P = 3. 321 × 10-8),advanced N1 stage( P = 9. 963 ×10-16) advanced c TNM stage( P = 2. 780 × 10-9),more residual cancer( P = 7. 481 × 10-3) and associated with poor disease free survival( HRhigh expression= 2. PHR= 0. 026 < 0. 05). Fibronectin 1 could regulate the gene sets such as NF-κB pathway,PI3 K/AKT pathway in TNF signaling,Claudin-1-Notch pathway-EMT in cell adhesion molecules and PAX8/PPARγ in thyroid hormone synthesis. The proofed experiments showed the mRNA transcription levels and protein expressions increased significantly,which illustrated in the thyroid cancer matrix. Conclusion: Upregulation of fibronectin 1 was found in thyroid cancer,in accordance with the pathways involved and played a potential prognostic marker.
引文
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[26] Vasko V,Espinosa AV,Scouten W,et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion[J]. Proc Natl Acad Sci USA,2007,104(8):2803-2808.
[27] Montemayor-Garcia C,Hardin H,Guo Z,et al. The role of epithelial mesenchymal transition markers in thyroid carcinoma progression[J]. Endocr Pathol,2013,24(4):206-212.
[28] Sponziello M,Rosignolo F,Celano M,et al. Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells[J]. Mol Cell Endocrinol,2016,431:123-132.
[29] Rivera M,Ricarte-Filho J,Tuttle RM,et al. Molecular,morphologic,and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension[J]. Thyroid,2010,20(10):1085-1093.
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[34] Ringel MD,Hayre N,Saito J,et al. Overexpression and overactivation of Akt in thyroid carcinoma[J]. Cancer Res,2001,61(16):6105-6111.
[35] Vasko V,Saji M,Hardy E,et al. Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer[J]. J Med Genet,2004,41(3):161-170.
[36] Saji M,Narahara K,Mccarty SK,et al. Akt1 deficiency delays tumor progression,vascular invasion,and distant metastasis in a murine model of thyroid cancer[J]. Oncogene,2011,30(42):4307-4315.
[37] Furuya F,Hanover JA,Cheng SY. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor[J]. Proc Natl Acad Sci USA,2006,103(6):1780-1785.
[38] Lv J,Sun B,Mai Z,et al. CLDN-1 promoted the epithelial to migration and mesenchymal transition(EMT)in human bronchial epithelial cells via Notch pathway[J]. Mol Cell Biochem,2017,432(1-2):91-98.
[39] Kroll TG,Sarraf P,Pecciarini L,et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma[J]. Science,2000,289(5483):1357-1360.
[40] Dobson ME,Diallo-Krou E,Grachtchouk V,et al. Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma[J]. Endocrinology,2011,152(11):4455-446.
[2] Jeon MJ,Kim WG,Choi YM,et al. Features predictive of distant metastasis in papillary thyroid microcarcinomas[J]. Thyroid,2016,26(1):161-168.
[3] Humphries MJ,Obara M,Olden K,et al. Role of fibronectin in adhesion,migration,and metastasis[J]. Cancer Invest,1989,7(4):373-393.
[4] Moursi AM,Damsky CH,Lull J,et al. Fibronectin regulates calvarial osteoblast differentiation[J]. J Cell Sci,1996,109(6):1369-1380.
[5] Brown RA,Jones KL. The synthesis and accumulation of fibronectin by human articular cartilage[J]. J Rheumatol,1990,17(1):65-72.
[6] Jerhammar F,Ceder R,Garvin S,et al. Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma[J]. Cancer Biol Ther,2010,10(12):1244-1251.
[7] Sonego M,Pellizzari I,Dall'Acqua A,et al. Common biological phenotypes characterize the acquisition of platinum-resistance in epithelial ovarian cancer cells[J]. Sci Rep,2017,7(1):7104.
[8] Yang Y,Li H,Hou S,et al. The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small cell lung cancer cell[J]. PLo S One,2013,8(5):e65309.
[9] Prasad ML,Pellegata NS,Huang Y,et al. Galectin-3,fibronectin-1,CITED-1,HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors[J]. Mod Pathol,2005,18(1):48-57.
[10] Xia S,Wang C,Postma EL,et al. Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis[J]. Onco Targets Ther,2017,10:1743-1755.
[11] Cooper L,Demicco EG,Saltz JH,et al. Pan-cancer insights from the cancer genome atlas:The pathologist's perspective[J]. J Pathol,2018,244(5):512-524.
[12] Omur O,Baran Y. An update on molecular biology of thyroid cancers[J]. Crit Rev Oncol Hematol,2014,90(3):233-252.
[13] Jemal A,Siegel R,Xu J,et al. Cancer statistics,2010[J]. CA Cancer J Clin,2010,60(5):277-300.
[14] Meas T,Vercellino L,Faugeron I,et al. The 2009 revised American thyroid association guidelines for thyroid cancer:Multifocality in T1tumors in question,for or against a more minimalist approach[J]? Thyroid,2013,23(8):1042-1043.
[15] Mian C,Barollo S,Pennelli G,et al. Molecular characteristics in papillary thyroid cancers(PTCs)with no131I uptake[J]. Clin Endocrinol(Oxf),2008,68(1):108-116.
[16] Huang Y,Prasad M,Lemon WJ,et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles[J]. Proc Natl Acad Sci USA,2001,98(26):15044-15049.
[17] Ryu S,Jimi S,Takebayashi S. Thyroid carcinoma distinctively expresses intracellular fibronectin in vivo[J]. Cancer Lett,1997,121(2):189-193.
[18] Rodrigues R,Roque L,Espadinha C,et al. Comparative genomic hybridization,BRAF,RAS,RET,and oligo-array analysis in aneuploid papillary thyroid carcinomas[J]. Oncol Rep,2007,18(4):917-926.
[19] Wasenius VM,Hemmer S,Kettunen E,et al. Hepatocyte growth factor receptor,matrix metalloproteinase-11,tissue inhibitor of metalloproteinase-1,and fibronectin are up-regulated in papillary thyroid carcinoma:A c DNA and tissue microarray study[J].Clin Cancer Res,2003,9(1):68-75.
[20] Prasad ML,Pellegata NS,Huang Y,et al. Galectin-3,fibronectin-1,CITED-1,HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors[J].Mod Pathol,2005,18(1):48-57.
[21] Liu YY,Morreau H,Kievit J,et al. Combined immunostaining with galectin-3,fibronectin-1,CITED-1,Hector Battifora mesothelial-1,cytokeratin-19,peroxisome proliferator-activated receptor,and sodium/iodide symporter antibodies for the differential diagnosis of non-medullary thyroid carcinoma[J]. Eur J Endocrinol,2008,158(3):375-384.
[22] Takano T,Miyauchi A,Yokozawa T,et al. Accurate and objective preoperative diagnosis of thyroid papillary carcinomas by reverse transcription-PCR detection of oncofetal fibronectin messenger RNA in fine-needle aspiration biopsies[J]. Cancer Res,1998,58(21):4913-4917.
[23] Hanahan D,Weinberg RA. Hallmarks of cancer:The next generation[J]. Cell,2011,144(5):646-674.
[24] Hwang HS,Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer[J]. Laryngoscope,2011,121(3):487-491.
[25] Jeon M,Lee J,Nam SJ,et al. Induction of fibronectin by HER2overexpression triggers adhesion and invasion of breast cancer cells[J]. Exp Cell Res,2015,333(1):116-126.
[26] Vasko V,Espinosa AV,Scouten W,et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion[J]. Proc Natl Acad Sci USA,2007,104(8):2803-2808.
[27] Montemayor-Garcia C,Hardin H,Guo Z,et al. The role of epithelial mesenchymal transition markers in thyroid carcinoma progression[J]. Endocr Pathol,2013,24(4):206-212.
[28] Sponziello M,Rosignolo F,Celano M,et al. Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells[J]. Mol Cell Endocrinol,2016,431:123-132.
[29] Rivera M,Ricarte-Filho J,Tuttle RM,et al. Molecular,morphologic,and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension[J]. Thyroid,2010,20(10):1085-1093.
[30] Musholt TJ,Fottner C,Weber MM,et al. Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules[J]. World J Surg,2010,34(11):2595-2603.
[31] Karin M. NF-kappaB as a critical link between inflammation and cancer[J]. Cold Spring Harb Perspect Biol,2009,1(5):a141.
[32] Mitsiades CS,Mcmillin D,Kotoula V,et al. Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro[J]. J Clin Endocrinol Metab,2006,91(10):4013-4021.
[33] Liu D,Xing M. Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-kappaB pathways[J]. Thyroid,2008,18(8):853-864.
[34] Ringel MD,Hayre N,Saito J,et al. Overexpression and overactivation of Akt in thyroid carcinoma[J]. Cancer Res,2001,61(16):6105-6111.
[35] Vasko V,Saji M,Hardy E,et al. Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer[J]. J Med Genet,2004,41(3):161-170.
[36] Saji M,Narahara K,Mccarty SK,et al. Akt1 deficiency delays tumor progression,vascular invasion,and distant metastasis in a murine model of thyroid cancer[J]. Oncogene,2011,30(42):4307-4315.
[37] Furuya F,Hanover JA,Cheng SY. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor[J]. Proc Natl Acad Sci USA,2006,103(6):1780-1785.
[38] Lv J,Sun B,Mai Z,et al. CLDN-1 promoted the epithelial to migration and mesenchymal transition(EMT)in human bronchial epithelial cells via Notch pathway[J]. Mol Cell Biochem,2017,432(1-2):91-98.
[39] Kroll TG,Sarraf P,Pecciarini L,et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma[J]. Science,2000,289(5483):1357-1360.
[40] Dobson ME,Diallo-Krou E,Grachtchouk V,et al. Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma[J]. Endocrinology,2011,152(11):4455-446.