Overexpression of LncRNA HOTAIR is Associated with Poor Prognosis in Thyroid Carcinoma: A Study Based on TCGA and GEO Data

Abstract

The role of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) in thyroid carcinoma (TC) remains unclear. The current study was aimed to assess the clinical value of HOTAIR expression levels in TC based on publically available data and to evaluate its potential signaling pathways. The expression data of HOTAIR and clinical information concerning TC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Furthermore, 3 online biological databases, Starbase, Cbioportal, and Multi Experiment Matrix, were used to identify HOTAIR-related genes in TC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Panther pathway analyses were then undertaken to study the most enriched signaling pathways in TC (EASE score<0.1, Bonferroni<0.05). The TCGA results demonstrated that the expression level of HOTAIR in TC tissues was significantly increased compared with non-cancerous tissues (p<0.001). HOTAIR over-expression was significantly associated with poor survival in TC patients (p=0.03). Meta-analyses of GEO datasets revealed a trend consistent with the above results on HOTAIR expression levels in TC (SMD=0.23; 95%CI, 0.00–0.45; p=0.047). Finally, the results of functional analysis for HOTAIR-related genes indicated that HOTAIR might participate in tumorigenesis via the Wnt signaling pathway. In conclusion, our study demonstrates that HOTAIR may be involved in thyroid carcinogenesis, and the over-expression of HOTAIR could act as a biomarker associated with a poor outcome in TC patients. Moreover, the Wnt signaling pathway may be the key pathway regulated by HOTAIR in TC.

Key words

LncRNA - HOTAIR - thyroid carcinoma - TCGA - microarray - prognosis

^* Hong-mei Li and Hong Yang contributed equally to this work.

• References

• 1 Konturek A, Barczynski M, Stopa M, Nowak W. Trends in prevalence of thyroid cancer over three decades: A retrospective cohort study of 17,526 surgical patients. World J Surg 2016; 40: 538-544
• 2 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: 2187-2195
• 3 Mutalib NS, Yusof AM, Mokhtar NM, Harun R, Muhammad R, Jamal R. Micrornas and lymph node metastasis in papillary thyroid cancers. Asian Pacific J Cancer Prevent 2016; 17: 25-35
• 4 Riesco-Eizaguirre G, Santisteban P. Molecular biology of thyroid cancer initiation. Clin Translat Oncol 2007; 9: 686-693
• 5 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013; 13: 184-199
• 6 Wang C, Yan G, Zhang Y, Jia X, Bu P. Long non-coding rna meg3 suppresses migration and invasion of thyroid carcinoma by targeting of rac1. Neoplasma 2015; 62: 541-549
• 7 Jendrzejewski J, Thomas A, Liyanarachchi S, Eiterman A, Tomsic J, He H, Radomska HS, Li W, Nagy R, Sworczak K, de la Chapelle A. Ptcsc3 is involved in papillary thyroid carcinoma development by modulating s100a4 gene expression. J Clin Endocrinol Metab 2015; 100: E1370-E1377
• 8 Zheng H, Wang M, Jiang L, Chu H, Hu J, Ning J, Li B, Wang D, Xu J. Braf-activated long noncoding rna modulates papillary thyroid carcinoma cell proliferation through regulating thyroid stimulating hormone receptor. Cancer Res Treat 2016; 48: 698-707
• 9 Zhou Q, Chen J, Feng J, Wang J. Long noncoding rna pvt1 modulates thyroid cancer cell proliferation by recruiting ezh2 and regulating thyroid-stimulating hormone receptor (tshr). Tumour Biol 2016; 37: 3105-3113
• 10 Lan X, Sun W, Zhang P, He L, Dong W, Wang Z, Liu S, Zhang H. Downregulation of long noncoding rna nonhsat037832 in papillary thyroid carcinoma and its clinical significance. Tumour Biol 2016; 37: 6117-6123
• 11 Kim D, Lee WK, Jeong S, Seol MY, Kim H, Kim KS, Lee EJ, Lee J, Jo YS. Upregulation of long noncoding rna loc100507661 promotes tumor aggressiveness in thyroid cancer. Mol Cell Endocrinol 2016; 431: 36-45
• 12 Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding rna as modular scaffold of histone modification complexes. Science 2010; 329: 689-693
• 13 Tang L, Zhang W, Su B, Yu B. Long noncoding rna hotair is associated with motility, invasion, and metastatic potential of metastatic melanoma. BioMed Res Int 2013; 251098
• 14 Ge XS, Ma HJ, Zheng XH, Ruan HL, Liao XY, Xue WQ, Chen YB, Zhang Y, Jia WH. Hotair, a prognostic factor in esophageal squamous cell carcinoma, inhibits wif-1 expression and activates wnt pathway. Cancer Sci 2013; 104: 1675-1682
• 15 Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY. Long non-coding rna hotair reprograms chromatin state to promote cancer metastasis. Nature 2010; 464: 1071-1076
• 16 Liu XH, Liu ZL, Sun M, Liu J, Wang ZX, De W. The long non-coding rna hotair indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer 2013; 13: 464
• 17 Qiu JJ, Lin YY, Ye LC, Ding JX, Feng WW, Jin HY, Zhang Y, Li Q, Hua KQ. Overexpression of long non-coding rna hotair predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer. Gynecol Oncol 2014; 134: 121-128
• 18 Wu ZH, Wang XL, Tang HM, Jiang T, Chen J, Lu S, Qiu GQ, Peng ZH, Yan DW. Long non-coding rna hotair is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. Oncol Rep 2014; 32: 395-402
• 19 Ishibashi M, Kogo R, Shibata K, Sawada G, Takahashi Y, Kurashige J, Akiyoshi S, Sasaki S, Iwaya T, Sudo T, Sugimachi K, Mimori K, Wakabayashi G, Mori M. Clinical significance of the expression of long non-coding rna hotair in primary hepatocellular carcinoma. Oncol Rep 2013; 29: 946-950
• 20 Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, Kim IF, Soboleva A, Tomashevsky M, Edgar R. Ncbi geo: Mining tens of millions of expression profiles – database and tools update. Nucleic Acids Res 2007; 35: D760-D765
• 21 Boyle J. Gene-expression omnibus integration and clustering tools in seqexpress. Bioinformatics 2005; 21: 2550-2551
• 22 Cancer Genome Atlas Research N. Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The cancer genome atlas pan-cancer analysis project. Nat Genet 2013; 45: 1113-1120
• 23 Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MD, Niu B, McLellan MD, Uzunangelov V, Zhang J, Kandoth C, Akbani R, Shen H, Omberg L, Chu A, Margolin AA, Van’t Veer LJ, Lopez-Bigas N, Laird PW, Raphael BJ, Ding L, Robertson AG, Byers LA, Mills GB, Weinstein JN, Van Waes C, Chen Z, Collisson EA. Cancer Genome Atlas Research N. Benz CC, Perou CM, Stuart JM. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 2014; 158: 929-944
• 24 Li JH, Liu S, Zhou H, Qu LH, Yang JH. Starbase v2.0: Decoding mirna-cerna, mirna-ncrna and protein-rna interaction networks from large-scale clip-seq data. Nucleic Acids Res 2014; 42: D92-D97
• 25 Adler P, Kolde R, Kull M, Tkachenko A, Peterson H, Reimand J, Vilo J. Mining for coexpression across hundreds of datasets using novel rank aggregation and visualization methods. Genome Biol 2009; 10: R139
• 26 Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex cancer genomics and clinical profiles using the cbioportal. Sci Signal 2013; 6: pl1
• 27 Agha A, Jung EM, Janke M, Hornung M, Georgieva M, Schlitt HJ, Schreyer AG, Strosczcynski C, Schleder S. Preoperative diagnosis of thyroid adenomas using high resolution contrast-enhanced ultrasound (ceus). Clin Hemorheol Microcircul 2013; 55: 403-409
• 28 Wang N, Xu Y, Ge C, Guo R, Guo K. Association of sonographically detected calcification with thyroid carcinoma. Head Neck 2006; 28: 1077-1083
• 29 Li X, Wang Z. The role of noncoding rna in thyroid cancer. Gland Surg 2012; 1: 146-150
• 30 Zhang R, Hardin H, Chen J, Guo Z, Lloyd RV. Non-coding rnas in thyroid cancer. Endocr Pathol 2016; 27: 12-20
• 31 He J, Zhou M, Chen X, Yue D, Yang L, Qin G, Zhang Z, Gao Q, Wang D, Zhang C, Huang L, Wang L, Zhang B, Yu J, Zhang Y. Inhibition of sall4 reduces tumorigenicity involving epithelial-mesenchymal transition via wnt/beta-catenin pathway in esophageal squamous cell carcinoma. J Exp Clin Cancer Res 2016; 35: 98
• 32 Hardin H, Guo Z, Shan W, Montemayor-Garcia C, Asioli S, Yu XM, Harrison AD, Chen H, Lloyd RV. The roles of the epithelial-mesenchymal transition marker prrx1 and mir-146b-5p in papillary thyroid carcinoma progression. Am J Pathol 2014; 184: 2342-2354
• 33 Li Q, Wu J, Wei P, Xu Y, Zhuo C, Wang Y, Li D, Cai S. Overexpression of forkhead box c2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition. Am J Cancer Res 2015; 5: 2022-2034
• 34 Zhang W, Jiao D, Liu B, Sun S. Analysis of risk factors contributing to recurrence of papillary thyroid carcinoma in chinese patients who underwent total thyroidectomy. Med Sci Monitor 2016; 22: 1274-1279
• 35 Nixon I. The Surgical Approach to Differentiated Thyroid Cancer. [version 1; referees: 3 approved] F1000Research 2015; 4 (F1000 Faculty Rev):1366 (doi: 10.12688/f1000research. 7002. 1)
• 36 Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY. Functional demarcation of active and silent chromatin domains in human hox loci by noncoding rnas. Cell 2007; 129: 1311-1323
• 37 Lee M, Kim HJ, Kim SW, Park SA, Chun KH, Cho NH, Song YS, Kim YT. The long non-coding rna hotair increases tumour growth and invasion in cervical cancer by targeting the notch pathway. Oncotarget 2016; 7: 44558-44571
• 38 Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012; 149: 1192-1205
• 39 Ishigaki K, Namba H, Nakashima M, Nakayama T, Mitsutake N, Hayashi T, Maeda S, Ichinose M, Kanematsu T, Yamashita S. Aberrant localization of beta-catenin correlates with overexpression of its target gene in human papillary thyroid cancer. J Clin Endocrinol Metab 2002; 87: 3433-3440
• 40 Chen G, Jiang Q, You Z, Yao J, Mou L, Lin X, Shen X, You T, Lin Q, Wen J, Lin L. Regulation of gsk-3 beta in the proliferation and apoptosis of human thyrocytes investigated using a gsk-3 beta-targeting rnai adenovirus expression vector: Involvement the wnt/beta-catenin pathway. Mol Biol Rep 2010; 37: 2773-2779
• 41 Kim WB, Lewis CJ, McCall KD, Malgor R, Kohn AD, Moon RT, Kohn LD. Overexpression of wnt-1 in thyrocytes enhances cellular growth but suppresses transcription of the thyroperoxidase gene via different signaling mechanisms. J Endocrinol 2007; 193: 93-106
• 42 Rao AS, Kremenevskaja N, von Wasielewski R, Jakubcakova V, Kant S, Resch J. Brabant G. Wnt/beta-catenin signaling mediates antineoplastic effects of imatinib mesylate (gleevec) in anaplastic thyroid cancer. J Clin Endocrinol Metab 2006; 91: 159-168
• 43 Tartari CJ, Donadoni C, Manieri E, Mologni L, Mina PD, Villa A, Gambacorti-Passerini C. Dissection of the ret/beta-catenin interaction in the tpc1 thyroid cancer cell line. Am J Cancer Res 2011; 1: 716-725
• 44 Zhang J, Gill AJ, Issacs JD, Atmore B, Johns A, Delbridge LW, Lai R, McMullen TP. The wnt/beta-catenin pathway drives increased cyclin d1 levels in lymph node metastasis in papillary thyroid cancer. Hum Pathol 2012; 43: 1044-1050
• 45 Ji M, Feng Q, He G, Yang L, Tang W, Lao X, Zhu D, Lin Q, Xu P, Wei Y, Xu J. Silencing homeobox c6 inhibits colorectal cancer cell proliferation. Oncotarget 2016; 7: 29216-29227
• 46 Joo MK, Park JJ, Yoo HS, Lee BJ, Chun HJ, Lee SW, Bak YT. The roles of hoxb7 in promoting migration, invasion and anti-apoptosis in gastric cancer. J Gastroenterol Hepatol 2016; 31: 1717-1726
• 47 Li H, Shen LY, Yan WP, Dong B, Kang XZ, Dai L, Yang YB, Fu H, Yang HL, Zhou HT, Huang C, Liang Z, Xiong HC, Chen KN. Deregulated hoxb7 expression predicts poor prognosis of patients with esophageal squamous cell carcinoma and regulates cancer cell proliferation in vitro and in vivo. PloS one 2015; 10: e0130551
• 48 Kim DY, Choi SJ, Kim SH, Chung HY, Yi S, Kim DW, Kim CC, Han TH. Upregulated hoxc4 induces cd14 expression during the differentiation of acute promyelocytic leukemia cells. Leukem Lymp 2005; 46: 1061-1066
• 49 Moon SM, Ahn MY, Kwon SM, Kim SA, Ahn SG, Yoon JH. Homeobox c5 expression is associated with the progression of 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. J Oral Pathol Med 2012; 41: 470-476
• 50 Bell D, Bell A, Roberts D, Weber RS, El-Naggar AK. Developmental transcription factor en1 – a novel biomarker in human salivary gland adenoid cystic carcinoma. Cancer 2012; 118: 1288-1292
• 51 Wang X, Xia Y. Microrna-328 inhibits cervical cancer cell proliferation and tumorigenesis by targeting tcf7l2. Biochem Biophys Res Commun 2016; 475: 169-175