The Identification of Three Key Genes Related to Stemness in Thyroid Carcinoma through Comprehensive Analysis

Tonglong       Zhang; Chunhong       Yan; Zhengdu       Ye; Xingling       Yin; Tian-an       Jiang

doi:10.2174/1386207323666200806164003

Abstract

Background: Tumor heterogeneity imposes great challenges on cancer treatment. Cancer stem cells (CSCs) are a leading factor contributing to tumor occurrence. However, the mechanisms underlying the growth of thyroid cancer (TCHA) are still unclear.

Methods: Key genes regulating the characteristics of THCA, such as stemness were identified by combining gene expressions of samples downloaded from the Cancer Genome Atlas (TCGA) and were used to establish an mRNA expression stemness index (mRNAsi) through machine learningbased methods. The relationships of mRNAsi, THCA clinical features and molecular subtypes were analyzed. Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to obtain mRNAsi-related gene modules and determine mRNAsi-related differentially co-expressed genes. Key genes related to mRNAsi were screened by protein interaction network. Functional analysis was conducted and expressions of key genes were verified in multiple external data sets.

Results: The mRNAsi score, which was found to be lower in the TCHA tissues than that in normal tissues (p<0.05), was positively correlated with a slow progression of tumor prognosis (p=0.0085). We screened a total of 83 differentially co-expressed genes related to mRNAsi and multiple tumor pathways such as apoptosis, tight junction, cytokine-cytokine receptor interaction, and cAMP signaling pathway (p<0.05). Finally, 28 protein interaction networks incorporating 32 genes were established, and 3 key genes were identified through network mining. 3 core genes were finally determined, as their low expressions were strongly correlated with the progression of THCA.

Conclusion: The study found that NGF, FOS, and GRIA1 are closely related to the characteristics of THCA stem cells. These genes, especially FOS, are highly indicative of the prognosis of THCA patients. Thus, screening therapy could be used to inhibit the stemness of TCHA.

Keywords: Bioinformatics, stemness, prognostic markers, TCGA, thyroid carcinoma, TCHA.

« Previous Next »

[1] 
Erica; K.M.; Reeves; Eric; P.; Hoffman; Kanneboyina; Nagaraju; Jesse; M. Corrigendum to “VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid”. Bioorg. Med. Chem. 21 (2013) 2241–2249 Bioorg. Med. Chem.,  2015, 23(7)
[2] 
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs. Future Med. Chem.,  2013, 5(8), 961-978.
[http://dx.doi.org/10.4155/fmc.13.62] [PMID:  23682571] 
[3] 
Ali, I.; Wani, W.A.; Saleem, K.; Hsieh, M.F. Anticancer metallodrugs of glutamic acid sulphonamides: in silico, DNA binding, hemolysis and anticancer studies. RSC Adv,  2014, 4(56), 29629.
[http://dx.doi.org/10.1039/C4RA02570A] 
[4] 
Ali, I.; Haque, A.; Wani, W.A.; Saleem, K.; Al Za’abi, M. Analyses of anticancer drugs by capillary electrophoresis: a review. Biomed. Chromatogr.,  2013, 27(10), 1296-1311.
[http://dx.doi.org/10.1002/bmc.2953] [PMID:  23843248] 
[5] 
Ali, I.; Haque, A.; Saleem, K.; Hsieh, M.F. Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: synthesis, pharmacological and simulation studies. Bioorg. Med. Chem.,  2013, 21(13), 3808-3820.
[http://dx.doi.org/10.1016/j.bmc.2013.04.018] [PMID:  23643901] 
[6] 
Ali, I.; Saleem, K.; Wesselinova, D.; Haque, A. Synthesis, DNA binding, hemolytic, and anti-cancer assays of curcumin I-based ligands and their ruthenium(III) complexes. Med. Chem. Res.,  2013, 22(3), 1386-1398.
[http://dx.doi.org/10.1007/s00044-012-0133-8] 
[7] 
Ali, I.; Wani, W.A.; Saleem, K.; Hseih, M.F. Design and synthesis of thalidomide based dithiocarbamate Cu(II), Ni(II) and Ru(III) complexes as anticancer agents. Polyhedron,  2013, 56, 134-143.
[8] 
Ali, I.; Wani, A.W.; Saleem, K.; Haque, A. Thalidomide: A banned drug resurged into future anticancer drug. Curr. Drug Ther.,  2012, 7(1), 13-23.
[http://dx.doi.org/10.2174/157488512800389164] 
[9] 
Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Al-Warthan, A.; Sanagi, M.M. Heterocyclic Scaffolds: Centrality in Anticancer Drug Development. Curr. Drug Targets,  2015, 16(7), 711-734.
[http://dx.doi.org/10.2174/1389450116666150309115922] [PMID:  25751009] 
[10] 
Ali, I. Nano anti-cancer drugs: pros and cons and future perspectives. Curr. Cancer Drug Targets,  2011, 11(2), 131-134.
[http://dx.doi.org/10.2174/156800911794328457] [PMID:  21062238] 
[11] 
Imran Ali, H.Y.A-E. Ashraf Ghanem, Enantioselective toxicity and carcinogenesis. Curr. Pharm. Anal.,  2005, 1(1), 109-125.
[http://dx.doi.org/10.2174/1573412052953328] 
[12] 
Ali, I. Nano drugs: novel agents for cancer chemo-therapy. Curr. Cancer Drug Targets,  2011, 11(2), 130.
[http://dx.doi.org/10.2174/156800911794328466] [PMID:  21247391] 
[13] 
Saleem, K.; Wani, W.A.; Haque, A.; Lone, M.N.; Hsieh, M.F.; Jairajpuri, M.A.; Ali, I. Synthesis, DNA binding, hemolysis assays and anticancer studies of copper(II), nickel(II) and iron(III) complexes of a pyrazoline-based ligand. Future Med. Chem.,  2013, 5(2), 135-146.
[http://dx.doi.org/10.4155/fmc.12.201] [PMID:  23360139] 
[14] 
Ali, I.; Wani, W.A.; Khan, A.; Haque, A.; Ahmad, A.; Saleem, K.; Manzoor, N. Synthesis and synergistic antifungal activities of a pyrazoline based ligand and its copper(II) and nickel(II) complexes with conventional antifungals. Microb. Pathog.,  2012, 53(2), 66-73.
[http://dx.doi.org/10.1016/j.micpath.2012.04.005] [PMID:  22575887] 
[15] 
Antonelli, A.; La Motta, C. Novel therapeutic clues in thyroid carcinomas: The role of targeting cancer stem cells. Med. Res. Rev.,  2017, 37(6), 1299-1317.
[http://dx.doi.org/10.1002/med.21448] [PMID:  28586525] 
[16] 
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin.,  2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID:  21296855] 
[17] 
La Vecchia, C.; Malvezzi, M.; Bosetti, C.; Garavello, W.; Bertuccio, P.; Levi, F.; Negri, E. Thyroid cancer mortality and incidence: a global overview. Int. J. Cancer,  2015, 136(9), 2187-2195.
[http://dx.doi.org/10.1002/ijc.29251] [PMID:  25284703] 
[18] 
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin.,  2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID:  29313949] 
[19] 
Tuttle, R.M.; Ball, D.W.; Byrd, D.; Dilawari, R.A.; Doherty, G.M.; Duh, Q.Y.; Ehya, H.; Farrar, W.B.; Haddad, R.I.; Kandeel, F.; Kloos, R.T.; Kopp, P.; Lamonica, D.M.; Loree, T.R.; Lydiatt, W.M.; McCaffrey, J.C.; Olson, J.A., Jr; Parks, L.; Ridge, J.A.; Shah, J.P.; Sherman, S.I.; Sturgeon, C.; Waguespack, S.G.; Wang, T.N.; Wirth, L.J. National Comprehensive Cancer Network. Thyroid carcinoma. J. Natl. Compr. Canc. Netw.,  2010, 8(11), 1228-1274.
[http://dx.doi.org/10.6004/jnccn.2010.0093] [PMID:  21081783] 
[20] 
Xing, M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer,  2013, 13(3), 184-199.
[http://dx.doi.org/10.1038/nrc3431] [PMID:  23429735] 
[21] 
Cabanillas, M.E.; McFadden, D.G.; Durante, C. Thyroid cancer. Lancet,  2016, 388(10061), 2783-2795.
[http://dx.doi.org/10.1016/S0140-6736(16)30172-6] [PMID:  27240885] 
[22] 
Malta, T.M.; Sokolov, A.; Gentles, A.J.; Burzykowski, T.; Poisson, L.; Weinstein, J.N.; Kaminska, B.; Huelsken, J.; Omberg, L.; Gevaert, O.; Colaprico, A.; Czerwinska, P.; Mazurek, S.; Mishra, L.; Heyn, H.; Krasnitz, A.; Godwin, A.K.; Lazar, A.J. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell,  2018, 173(2), 338-354.
[23] 
Bjerkvig, R.; Tysnes, B.B.; Aboody, K.S.; Najbauer, J.; Terzis, A.J. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat. Rev. Cancer,  2005, 5(11), 899-904.
[http://dx.doi.org/10.1038/nrc1740] [PMID:  16327766] 
[24] 
Thorsson, V.; Gibbs, D.L.; Brown, S.D.; Wolf, D.; Bortone, D.S.; Ou Yang,  T.H.; Porta-Pardo, E.; Gao, G.F.; Plaisier, C.L.; Eddy, J.A.; Ziv, E.; Culhane, A.C.; Paull, E.O.; Sivakumar, I.K.A.; Gentles, A.J.; Malhotra, R.; Farshidfar, F.; Colaprico, A.; Parker, J.S.; Mose, L.E.; Vo, N.S.; Liu, J.; Liu, Y.; Rader, J.; Dhankani, V.; Reynolds, S.M.; Bowlby, R.; Califano, A.; Cherniack, A.D.; Anastassiou, D.; Bedognetti, D.; Mokrab, Y.; Newman, A.M.; Rao, A.; Chen, K.; Krasnitz, A.; Hu, H.; Malta, T.M.; Noushmehr, H.; Pedamallu, C.S.; Bullman, S.; Ojesina, A.I.; Lamb, A.; Zhou, W.; Shen, H.; Choueiri, T.K.; Weinstein, J.N.; Guinney, J.; Saltz, J.; Holt, R.A.; Rabkin, C.S.; Lazar, A.J.; Serody, J.S.; Demicco, E.G.; Disis, M.L.; Vincent, B.G.; Shmulevich, I. Cancer genome atlas research network. the immune landscape of cancer. Immunity,  2019, 51(2), 411-412.
[http://dx.doi.org/10.1016/j.immuni.2019.08.004] [PMID:  31433971] 
[25] 
Hwangbo, Y.; Park, Y.J. Genome-wide association studies of autoimmune thyroid diseases, thyroid function, and thyroid cancer. genome-wide association studies of autoimmune thyroid diseases, thyroid function, and thyroid cancer. Endocrinol. Metab. (Seoul),  2018, 33(2), 175-184.
[http://dx.doi.org/10.3803/EnM.2018.33.2.175] [PMID:  29947174] 
[26] 
Babli, S.; Payne, R.J.; Mitmaker, E.; Rivera, J. Effects of chronic lymphocytic thyroiditis on the clinicopathological features of papillary thyroid cancer. Eur. Thyroid J.,  2018, 7(2), 95-101.
[http://dx.doi.org/10.1159/000486367] [PMID:  29594061] 
[27] 
Bai, Y.; Guo, T.; Huang, X.; Wu, Q.; Niu, D.; Ji, X.; Feng, Q.; Li, Z.; Kakudo, K. In papillary thyroid carcinoma, expression by immunohistochemistry of BRAF V600E, PD-L1, and PD-1 is closely related. Virchows Arch.,  2018, 472(5), 779-787.
[http://dx.doi.org/10.1007/s00428-018-2357-6] [PMID:  29651624] 
[28] 
Rotondi, M.; Coperchini, F.; Latrofa, F.; Chiovato, L. Role of chemokines in thyroid cancer microenvironment: is cxcl8 the main player? Front. Endocrinol. (Lausanne),  2018, 9, 314.
[http://dx.doi.org/10.3389/fendo.2018.00314] [PMID:  29977225] 
[29] 
Kim, J.; Bae, J.S. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm.,  2016, 20166058147
[http://dx.doi.org/10.1155/2016/6058147] [PMID:  26966341] 
[30] 
Clough, E.; Barrett, T. The gene expression omnibus database. Methods Mol. Biol.,  2016, 1418, 93-110.
[http://dx.doi.org/10.1007/978-1-4939-3578-9_5] [PMID:  27008011] 
[31] 
Tomás, G.; Tarabichi, M.; Gacquer, D.; Hébrant, A.; Dom, G.; Dumont, J.E.; Keutgen, X.; Fahey, T.J., III; Maenhaut, C.; Detours, V. A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic. Oncogene,  2012, 31(41), 4490-4498.
[http://dx.doi.org/10.1038/onc.2011.626] [PMID:  22266856] 
[32] 
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell,  2014, 159(3), 676-690.
[http://dx.doi.org/10.1016/j.cell.2014.09.050] [PMID:  25417114] 
[33] 
Love, M.I.; Huber, W.; Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol.,  2014, 15(12), 550.
[http://dx.doi.org/10.1186/s13059-014-0550-8] [PMID:  25516281] 
[34] 
Diboun, I.; Wernisch, L.; Orengo, C.A.; Koltzenburg, M. Microarray analysis after RNA amplification can detect pronounced differences in gene expression using limma. BMC Genomics,  2006, 7, 252.
[http://dx.doi.org/10.1186/1471-2164-7-252] [PMID:  17029630] 
[35] 
Langfelder, P.; Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics,  2008, 9, 559.
[http://dx.doi.org/10.1186/1471-2105-9-559] [PMID:  19114008] 
[36] 
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS,  2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID:  22455463] 
[37] 
Yu, G.; Wang, L.G.; Yan, G.R.; He, Q.Y. DOSE: an R/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics,  2015, 31(4), 608-609.
[http://dx.doi.org/10.1093/bioinformatics/btu684] [PMID:  25677125] 
[38] 
Szklarczyk, D.; Franceschini, A.; Wyder, S.; Forslund, K.; Heller, D.; Huerta-Cepas, J.; Simonovic, M.; Roth, A.; Santos, A.; Tsafou, K.P.; Kuhn, M.; Bork, P.; Jensen, L.J.; von Mering, C. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res.,  2015, 43(Database issue), D447-D452.
[http://dx.doi.org/10.1093/nar/gku1003] [PMID:  25352553] 
[39] 
Szklarczyk, D.; Morris, J.H.; Cook, H.; Kuhn, M.; Wyder, S.; Simonovic, M.; Santos, A.; Doncheva, N.T.; Roth, A.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res.,  2017, 45(D1), D362-D368.
[http://dx.doi.org/10.1093/nar/gkw937] [PMID:  27924014] 
[40] 
Chin, C.H.; Chen, S.H.; Wu, H.H.; Ho, C.W.; Ko, M.T.; Lin, C.Y. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol.,  2014, 8(Suppl. 4), S11.
[http://dx.doi.org/10.1186/1752-0509-8-S4-S11] [PMID:  25521941] 
[41] 
Yarchoan, M.; Xing, D.; Luan, L.; Xu, H.; Sharma, R.B.; Popovic, A.; Pawlik, T.M.; Kim, A.K.; Zhu, Q.; Jaffee, E.M.; Taube, J.M.; Anders, R.A. Characterization of the Immune Microenvironment in Hepatocellular Carcinoma. Clin. Cancer Res.,  2017, 23(23), 7333-7339.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0950] [PMID:  28928158] 
[42] 
Leonardi, G.C.; Candido, S.; Cervello, M.; Nicolosi, D.; Raiti, F.; Travali, S.; Spandidos, D.A.; Libra, M. The tumor microenvironment in hepatocellular carcinoma. (review). Int. J. Oncol.,  2012, 40(6), 1733-1747.
[PMID: 22447316] 
[43] 
Miranda, A.; Hamilton, P.T.; Zhang, A.W.; Pattnaik, S.; Becht, E.; Mezheyeuski, A.; Bruun, J.; Micke, P.; de Reynies, A.; Nelson, B.H. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc. Natl. Acad. Sci. USA,  2019, 116(18), 9020-9029.
[http://dx.doi.org/10.1073/pnas.1818210116] [PMID:  30996127] 
[44] 
Salabè, G.B. Pathogenesis of thyroid nodules: histological classification? Biomed. Pharmacother.,  2001, 55(1), 39-53.
[http://dx.doi.org/10.1016/S0753-3322(00)00010-X] [PMID:  11237284] 
[45] 
Deligiorgi, M.V.; Mahaira, H.; Eftychiadis, C.; Kafiri, G.; Georgiou, G.; Theodoropoulos, G.; Konstadoulakis, M.M.; Zografos, E.; Zografos, G.C. RANKL, OPG, TRAIL, KRas, and c-Fos expression in relation to central lymph node metastases in papillary thyroid carcinoma. J. BUON,  2018, 23(4), 1029-1040.
[PMID: 30358208] 
[46] 
Tilley, S.K.; Kim, W.Y.; Fry, R.C. Analysis of bladder cancer tumor CpG methylation and gene expression within The Cancer Genome Atlas identifies GRIA1 as a prognostic biomarker for basal-like bladder cancer. Am. J. Cancer Res.,  2017, 7(9), 1850-1862.
[PMID: 28979808] 
[47] 
He, D.; Liu, L.; Wang, Y.; Sheng, M. A novel genes signature associated with the progression of polycystic ovary syndrome. Pathol. Oncol. Res.,  2020, 26(1), 575-582.
[http://dx.doi.org/10.1007/s12253-019-00676-3] [PMID:  31278444] 

Rights & Permissions Print Cite

Article Metrics

69

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207323666200806164003	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

The Identification of Three Key Genes Related to Stemness in Thyroid Carcinoma through Comprehensive Analysis

Abstract Play Pause

Related Journals

Related Articles

Abstract