Linc-ROR and its spliced variants 2 and 4 are significantly up-regulated in esophageal squamous cell carcinoma

Document Type : Original Article

Authors

1 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

2 Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

3 Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran

4 Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran

5 Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Similar characteristics of molecular pathways between cellular reprogramming events and tumorigenesis have been accentuated in recent years. Reprogramming-related transcription factors, also known as Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC), are also well-known oncogenes promoting cancer initiation, progression, and cellular transformation into cancer stem cells. Long non-coding RNAs (lncRNAs) are a major class of RNA molecules with emerging roles in stem cell pluripotency, cellular reprogramming, cellular transformation, and tumorigenesis. The long intergenic non-coding RNA ROR (lincRNA-ROR, linc-ROR) acts as a regulator of cellular reprograming through sponging miR-145 that normally negatively regulates the expression of the stemness factors NANOG, OCT4, and SOX2.
Materials and Methods: Here, we employed a real-time PCR approach to determine the expression patterns of linc-ROR and its two novel spliced variants (variants 2 and 4) in esophageal squamous cell carcinoma (ESCC).
Results: The quantitative real-time RT-PCR results revealed a significant up-regulation of linc-ROR (P=0.0098) and its variants 2 (P=0.0250) and 4 (P=0.0002) in tumor samples of ESCC, compared to their matched non-tumor tissues obtained from the margin of same tumors. Our data also demonstrated a significant up-regulation of variant 4 in high-grade tumor samples, in comparison to the low-grade ones (P=0.04). Moreover, the ROC curve analysis demonstrated that the variant 4 of ROR has a potential to discriminate between tumor and non-tumor samples (AUC=0.66, P<0.05). Conclusion: Our data suggest a significant up-regulation of linc-ROR and its variants 2 and 4 in ESCC tissue samples.

Keywords


1.Parkin DM, Bray F, Ferlay J, Pisani P.  Global cancer statistics, 2002. CA Cancer J Clin 2005; 55:74 – 108.
2.Kamangar F, Dores GM, Anderson WF.  Patterns  of cancer  incidence,  mortality,  and  prevalence  across  five continents: defining priorities to reduce cancer disparities in different  geographic  regions  of  the  world.  J Clin Oncol 2006; 24:2137–2150.
3.Semnani S, Sadjadi A, Fahimi S, Nouraie M, Naeimi M, Kabir J, et al. Declining incidence of esophageal cancer in the Turkmen Plain, eastern part of the Caspian Littoral of Iran: A retrospective cancer surveillance. Cancer Detect Prev 2006; 30:14-19.
4.Sadjadi A, Marjani H, Semnani S, Nasseri-Moghaddam S. Esophageal Cancer in Iran: A Review. Middle East J Cancer 2010; 1: 5-14.
5.Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663–676.
6.Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131:861–872.
7.Daley GQ. Common themes of dedifferentiation in somatic cell reprogramming and cancer. Cold Spring Harb Symp Quant Biol 2008; 73:171-174.
8.Castellanos A, Vicente-Duenas C, Campos-Sanchez E, Cruz JJ, Garcia-Criado FJ, Garcia-Cenador MB, et al. Cancer as a reprogramming-like disease: implications in tumor development and treatment. Semin Cancer Biol 2010; 20:93-97.
9.Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 2011; 477:295–300.
10.Hu W, Yuan B, Flygare J, Lodish HF. Long noncoding RNA mediated anti-apoptotic activity in murine erythroid terminal differentiation. Genes Dev 2011; 25:2573–2578.
11.Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, et al.  Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 2013; 152:570–583.
12.Sun L, Goff LA, Trapnell C, Alexander R, Lo KA, Hacisuleyman E, et al. Long noncoding RNAs regulate adipogenesis. Proc Natl Acad Sci U S A 2013; 110:3387–3392.
13.Ng SY, Johnson R, Stanton LW. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J 2012; 31:522–533.
14.Perez DS, Hoage TR, Pritchett JR, Ducharme-Smith AL, Halling ML, Ganapathiraju SC, et al. Long, abundantly expressed non-coding transcripts are altered in cancer. Hum Mol Genet 2007; 17:642–655.
15.Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov 2011; 1:391–407.
16.Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 2008; 105:716–721.
17.Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, et al. Large intergenic non-coding RNA-ROR modulates reprogramming of human induced pluripotent stem cell. Nat Genet 2010; 42:1113-1117.
18.Wang Y,?? et al. Endogenous miRNA sponge lincRNA-ROR regulates Oct4, Nanog and Sox2 in humanembryonic stem cell self-renewal. Dev Cell 2013; 25:69-80.
19.Lv XB, Lian GY, Wang HR, Song E, Yao H, Wang MH. Long noncoding RNA HOTAIR is a prognostic marker for esophageal squamous cell carcinoma progression and survival. PLoS One 2013; 8:e63516.
20.Chen FJ, Sun M, Li SQ, Wu QQ, Ji L, Liu ZL, et al. Up-regulation of the long non-coding RNA HOTAIR promotes esophageal squamous cell carcinoma metastasis and poor prognosis. Mol Carcinog 2013; 52:908-915.
21.Hu L, Wu Y, Tan D, Meng H, Wang K, Bai Y, et al. Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res 2015; 34:7.
22.Shi WH, Wu QQ, Li SQ, Yang TX, Liu ZH, Tong YS, et al. Up-regulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma. Tumour Biol 2015; 36:2501-2507.
23.Li JY, Ma X, Zhang CB. Overexpression of long non-coding RNA UCA1 predicts a poor prognosis in patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol 2014; 71:7938-7944.
24.Shahryari A, Rafiee MR, Fouani Y, Oliae NA, Samaei NM, Shafiee M, et al. Two novel splice variants of SOX2OT, SOX2OT‐S1, and SOX2OT‐S2 are coupregulated with SOX2 and OCT4 in esophageal squamous cell carcinoma. Stem Cells 2014; 32:126-134.
25.Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, et al. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis 2014; 5:e1287.
26.Takahashi K, Yan IK, Kogure T, Haga H, Patel T. Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio 2014; 4:458-467.
27.Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D, et al. The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage. Cell Res 2013; 23:340-350.
28.Feng S, Yao J, Chen Y, Geng P, Zhang H, Ma X, et al. Expression and functional role of reprogramming-related long noncoding RNA (lincRNA-ROR) in Glioma. J Mol Neurosci 2015; 56:623-630.