Abstract
The prognosis of non-small cell lung cancer (NSCLC) is still poor, and it is necessary to identify effectively diagnostic and prognostic biomarkers for NSCLC. Recent evidence demonstrates that long non-coding RNA (lncRNA) is actively transcribed from human genome. Some lncRNAs show a time- or tissue-specific expression manner and play important roles in diverse biological processes. Additionally, various cancer-associated lncRNAs have been identified, such as metastasis-associated lung adenocarcinoma transcript 1 for lung cancer. Here, we characterized the expression profile of a novel lncRNA, colon cancer-associated transcript 2 (CCAT2), in lung cancer and found that CCAT2 was significantly over-expressed in NSCLC tissues compared with paired adjacent normal tissues, with an average up-regulation fold of 7.5. Intriguingly, over-expression of CCAT2 was significantly associated with lung adenocarcinoma (p = 0.033) but not squamous cell cancer. Silencing CCAT2 by siRNA led to inhibition of proliferation and invasion in NSCLC cell lines in vitro. Additionally, CCAT2 combined with CEA could predict lymph node metastasis. Our findings indicate that CCAT2 is a lung adenocarcinoma-specific lncRNA and promotes invasion of NSCLC and highlight its potential as a biomarker for lymph node metastasis.
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References
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer. 1999;80(6):827–41.
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin. 2002;52(1):23–47.
Rosell R, Bivona TG, Karachaliou N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet. 2013;382(9893):720–31.
Yang X, Zhang Z, Qiu M, Hu J, Fan X, Wang J, et al. Glypican-5 Is a novel metastasis suppressor gene in non-small cell lung cancer. Cancer Lett. 2013;341(2):265–73.
Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1 % of the human genome by the Encode Pilot Project. Nature. 2007;447(7146):799–816.
Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.
Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–55.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6.
Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, et al. Androgen-responsive long noncoding RNA Ctbp1-as promotes prostate cancer. EMBO J. 2013;32(12):1665–80.
Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22(39):8031–41.
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329(5992):689–93.
Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73(3):1180–9.
Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology. 2007;132(1):330–42.
Geng YJ, Xie SL, Li Q, Ma J, Wang GY. Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res. 2011;39(6):2119–28.
Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18(5):1243–50.
Ren S, Wang F, Shen J, Sun Y, Xu W, Lu J, et al. Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer. Eur J Cancer. 2013. doi:10.1016/j.ejca.2013.04.026.
Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, et al. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 2011;6(12):1984–92.
Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013;23(9):1446–61.
Redis RS, Sieuwerts AM, Look MP, Tudoran O, Ivan C, Spizzo R, et al. CCAT2, a novel long non-coding RNA in breast cancer: expression study and clinical correlations. Oncotarget. 2013;4(10):1748–62.
Yin R, Zhang S, Wu Y, Fan X, Jiang F, Zhang Z, et al. Microrna-145 suppresses lung adenocarcinoma-initiating cell proliferation by targeting Oct4. Oncol Rep. 2011;25(6):1747–54.
Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629–41.
Qiu MT, Hu JW, Yin R, Xu L. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol. 2013;34(2):613–20.
Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F, et al. Repression of the long noncoding RNA—let by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 2013. doi:10.1016/j.molcel.2013.01.010.
Kretz M, Siprashvili Z, Chu C, Webster DE, Zehnder A, Qu K, et al. Control of somatic tissue differentiation by the long non-coding RNA Tincr. Nature. 2013;493(7431):231–5.
Wu W, Bhagat TD, Yang X, Song JH, Cheng Y, Agarwal R, et al. Hypomethylation of noncoding DNA Regions and overexpression of the long noncoding RNA, Afap1–As1, in Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology. 2013. doi:10.1053/j.gastro.2013.01.019.
Bertozzi D, Iurlaro R, Sordet O, Marinello J, Zaffaroni N, Capranico G. Characterization of novel antisense Hif-1alpha transcripts in human cancers. Cell Cycle. 2011;10(18):3189–97.
Guo F, Li Y, Liu Y, Wang J, Li G. Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in Caski human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai). 2010;42(3):224–9.
Ren S, Wang F, Shen J, Sun Y, Xu W, Lu J, et al. Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer. Eur J Cancer. 2013;49(13):2949–59.
Haiman CA, Le Marchand L, Yamamato J, Stram DO, Sheng X, Kolonel LN, et al. A common genetic risk factor for colorectal and prostate cancer. Nat Genet. 2007;39(8):954–6.
Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S, et al. A genome-wide association scan of tag Snps identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet. 2007;39(8):984–8.
Ghoussaini M, Song H, Koessler T, Al Olama AA, Kote-Jarai Z, Driver KE, et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J Natl Cancer Inst. 2008;100(13):962–6.
Zhang X, Chen Q, He C, Mao W, Zhang L, Xu X, et al. Polymorphisms on 8q24 are associated with lung cancer risk and survival in Han Chinese. PLoS One. 2012;7(7):e41930.
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This study is funded by the Natural Science Foundation of China (81372321, 81201830), Natural Science Foundation for High Education of Jiangsu Province (13KJB320010), Research and Innovation Program for Graduates of Jiangsu Province (CXLX13_571), Human Resource Summit Grant of Jiangsu Province (10-D-078), and Key Clinical Medicine Technology Foundation of Jiangsu Province (BL2012030).
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Mantang Qiu and Youtao Xu are contributed equally to this work
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Qiu, M., Xu, Y., Yang, X. et al. CCAT2 is a lung adenocarcinoma-specific long non-coding RNA and promotes invasion of non-small cell lung cancer. Tumor Biol. 35, 5375–5380 (2014). https://doi.org/10.1007/s13277-014-1700-z
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DOI: https://doi.org/10.1007/s13277-014-1700-z