Abstract
Retinoblastoma is the most frequently occurring tumour in the eyes in early childhood. Novel targets that are important for the diagnosis or treatment of retinoblastoma could be valuable in increasing the survival rate of patients affected by this disease. Long non-coding RNAs (lncRNAs) are a recently discovered type of RNAs with no protein-coding function; yet it has become increasingly clear that lncRNAs are responsible for important gene regulatory functions in various diseases. In this study, the expression of lncRNA HOTAIR was measured by qRT-PCR, and HOTAIR expression was found to be significantly upregulated in human retinoblastomas tissues as compared with that in paracancerous tissues. Knockdown of HOTAIR restricted the proliferation and invasion of the more invasive retinoblastoma Y79 cells, and led to G0/G1 arrest, possibly through inhibiting phospho-RB1, RB1 and CCNE. Furthermore, we found that the Notch signalling pathway was activated abnormally in retinoblastoma cell lines, while knockdown of HOTAIR attenuated the endogenous Notch signalling pathway in vitro and in vivo. In addition, knockdown of HOTAIR could inhibit the tumour progression in a xenograft model of retinoblastoma. In summary, our findings indicate that HOTAIR may play important roles in retinoblastoma progression via Notch pathway. HOTAIR has the potential to enhance the development of novel targeted diagnostic and therapeutic approaches for retinoblastoma.
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References
Antczak C, Kloepping C, Radu C, Genski T, Muller-Kuhrt L, Siems K, de Stanchina E, Abramson DH, et al. 2009 Revisiting old drugs as novel agents for retinoblastoma: in vitro and in vivo antitumor activity of cardenolides. Invest. Ophthalmol. Vis. Sci. 50 3065–3073
Bailey AM and Posakony JW 1995 Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev. 9 2609–2622
Berrondo C, Flax J, Kucherov V, Siebert A, Osinski T, Rosenberg A, Fucile C, Richheimer S, et al. 2016 Expression of the long Non-coding RNA HOTAIR correlates with disease progression in bladder cancer and is contained in bladder cancer patient urinary exosomes. PLoS One 11 e0147236
Chen J, Shen Z, Zheng Y, Wang S and Mao W 2015 Radiotherapy induced Lewis lung cancer cell apoptosis via inactivating beta-catenin mediated by upregulated HOTAIR. Int. J. Clin. Exp. Pathol. 8 7878–7886
de Jong MC, Kors WA, de Graaf P, Castelijns JA, Kivela T and Moll AC 2014 Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol. 15 1157–1167
Demarest RM, Ratti F and Capobianco AJ 2008 It's T-ALL about Notch. Oncogene. 27 5082–5091
Gao JZ, Li J, Du JL and Li XL 2016 Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence. Oncol. Lett. 11 1791–1798
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, et al. 2010 Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464 1071–1076
Hung T and Chang HY 2010 Long noncoding RNA in genome regulation: prospects and mechanisms. RNA Biol. 7 582–585
Jarriault S, Le Bail O, Hirsinger E, Pourquie O, Logeat F, Strong CF, Brou C, Seidah NG, et al. 1998 Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol. Cell. Biol. 18 7423–7431
Kandalam M, Mitra M, Subramanian K and Biswas J 2010 Molecular pathology of retinoblastoma. Middle East Afr J Ophthalmol. 17 217–223
Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S and Safe S 2013 HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 32 1616–1625
Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, Tanaka F, Shibata K, et al. 2011 Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71 6320–6326
Li H, An J, Wu M, Zheng Q, Gui X, Li T, Pu H and Lu D 2015 LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Oncotarget
Liu XH, Liu ZL, Sun M, Liu J, Wang ZX and De W 2013 The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer 13 464
Liu FT, Qui C, Zhang Y, Xia GF, Hao TF, Zhu PQ, and Luo HL 2016 The association of HOTAIR expression with clinicopathological features and prognosis in gastric cancer patients. Panminerva Med. 58 167–174
Lobry C, Oh P and Aifantis I 2011 Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J. Exp. Med. 208 1931–1935
Lu L, Zhu G, Zhang C, Deng Q, Katsaros D, Mayne ST, Risch HA, Mu L, et al. 2012 Association of large noncoding RNA HOTAIR expression and its downstream intergenic CpG island methylation with survival in breast cancer. Breast Cancer Res. Treat. 136 875–883
MacCarthy A, Birch JM, Draper GJ, Hungerford JL, Kingston JE, Kroll ME, Onadim Z, Stiller CA, et al. 2009 Retinoblastoma in Great Britain 1963-2002. Br. J. Ophthalmol. 93 33–37
Malusa F, Taranta M, Zaki N, Cinti C and Capobianco E 2015 Time-course gene profiling and networks in demethylated retinoblastoma cell line. Oncotarget 6 23688–23707
Nakagawa T, Endo H, Yokoyama M, Abe J, Tamai K, Tanaka N, Sato I, Takahashi S, et al. 2013 Large noncoding RNA HOTAIR enhances aggressive biological behavior and is associated with short disease-free survival in human non-small cell lung cancer. Biochem. Biophys. Res. Commun. 436 319–324
Niland CN, Merry CR and Khalil AM 2012 Emerging roles for long non-coding RNAs in cancer and neurological disorders. Front. Genet. 3 25
Ono H, Motoi N, Nagano H, Miyauchi E, Ushijima M, Matsuura M, Okumura S, Nishio M, et al. 2014 Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer. Cancer Med. 3 632–642
Pei J and Wang B 2015 Notch-1 promotes breast cancer cells proliferation by regulating LncRNA GAS5. Int. J. Clin. Exp. Med. 8 14464–14471
Rodriguez-Galindo C, Wilson MW, Chantada G, Fu L, Qaddoumi I, Antoneli C, Leal-Leal C, Sharma T, et al. 2008 Retinoblastoma: one world, one vision. Pediatrics 122 e763–e770
Sharma S, Mandal P, Sadhukhan T, Roy Chowdhury R, Ranjan Mondal N, Chakravarty B, Chatterjee T, Roy S, et al. 2015 Bridging links between long noncoding RNA HOTAIR and HPV oncoprotein E7 in cervical cancer pathogenesis. Sci. Rep. 5 11724
Shi X, Sun M, Liu H, Yao Y and Song Y 2013 Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett. 339 159–166
Shields CL, Lally SE, Leahey AM, Jabbour PM, Caywood EH, Schwendeman R and Shields JA 2014 Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr. Opin. Ophthalmol. 25 374–385
Suman S, Das TP and Damodaran C 2013 Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells. Br. J. Cancer 109 2587–2596
Sun X, Du P, Yuan W, Du Z, Yu M, Yu X and Hu T 2015 Long non-coding RNA HOTAIR regulates cyclin J via inhibition of microRNA-205 expression in bladder cancer. Cell Death Dis. 6 e1907
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, et al. 2010 Long noncoding RNA as modular scaffold of histone modification complexes. Science 329 689–693
Wang J, Fu L, Gu F and Ma Y 2011 Notch1 is involved in migration and invasion of human breast cancer cells. Oncol. Rep. 26 1295–1303
Wang Y, Wu P, Lin R, Rong L, Xue Y and Fang Y 2015 LncRNA NALT interaction with NOTCH1 promoted cell proliferation in pediatric T cell acute lymphoblastic leukemia. Sci. Rep. 5 13749
Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, et al. 2002 Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat. Med. 8 979–986
Xiao W, Chen X and He M 2014 Inhibition of the Jagged/Notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/betacatenin signaling pathways. Mol. Med. Rep. 10 453–458
Zhang JX, Han L, Bao ZS, Wang YY, Chen LY, Yan W, Yu SZ, Pu PY, et al. 2013 HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro-Oncology. 15 1595–1603
Zhao W, Song M, Zhang J, Kuerban M and Wang H 2015 Combined identification of long non-coding RNA CCAT1 and HOTAIR in serum as an effective screening for colorectal carcinoma. Int. J. Clin. Exp. Pathol. 8 14131–14140
Zhou C, Ye L, Jiang C, Bai J, Chi Y and Zhang H 2015 Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1alpha activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer. Tumour Biol. 36 9179–9188
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[Dong C, Liu S, Lv Y, Zhang C, Gao H, Tan L and Wang H 2016 Long non-coding RNA HOTAIR regulates proliferation and invasion via activating Notch signalling pathway in retinoblastoma. J. Biosci.]
Changxia Dong, Shaoyi Liu and Yongbin Lv contributed equally to this work.
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Dong, C., Liu, S., Lv, Y. et al. Long non-coding RNA HOTAIR regulates proliferation and invasion via activating Notch signalling pathway in retinoblastoma. J Biosci 41, 677–687 (2016). https://doi.org/10.1007/s12038-016-9636-7
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DOI: https://doi.org/10.1007/s12038-016-9636-7