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      The prognostic potential and carcinogenesis of long non-coding RNA TUG1 in human cholangiocarcinoma

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          Abstract

          Cholangiocarcinoma (CCA) is a fatal disease with increasing worldwide incidence and is characterized by poor prognosis due to its poor response to conventional chemotherapy or radiotherapy. Long non-coding RNAs (lncRNAs) play key roles in multiple human cancers, including CCA. Cancer progression related lncRNA taurine-up-regulated gene 1 (TUG1) was reported to be involved in human carcinomas. However, the impact of TUG1 in CCA is unclear. The aim of this study was to explore the expression pattern of TUG1 and evaluate its clinical significance as well as prognostic potential in CCA. In addition, the functional roles of TUG1 including cell proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT), were evaluated after TUG1 silencing. Our data demonstrated up-regulation of TUG1 in both CCA tissues and cell lines. Moreover, overexpression of TUG1 is linked to tumor size ( p=0.005), TNM stage ( p=0.013), postoperative recurrence ( p=0.036) and overall survival ( p=0.010) of CCA patients. Furthermore, down-regulation of TUG1 following RNA silencing reduced cell growth and increased apoptosis in CCA cells. Additionally, TUG1 suppression inhibited metastasis potential in vitro by reversing EMT. Overall, our results suggest that TUG1 may be a rational CCA-related prognostic factor and therapeutic target.

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          Most cited references36

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          Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.

          To assess long-term survival and prognostic factors in a large series of patients with bile duct cancer. The incidence of bile duct cancer is low but increasing. Determinants of survival vary in the literature, due to a lack of sufficient numbers of patients in most series. We studied 564 consecutive patients with bile duct cancer operated upon between 1973 and 2004. Patients were divided into intrahepatic, perihilar, and distal groups. Principle outcome measures were complications, 30-day mortality, and survival. Of the 564 patients, 44 (8%) had intrahepatic, 281 (50%) had perihilar, and 239 (42%) had distal tumors. Approximately half (294, 52%) were treated before 1995, while 270 (48%) were treated thereafter. The perioperative mortality rate was 4%. In log-rank analyses, survival was higher in the later time period (P = 0.002), in patients with intrahepatic disease (P = 0.001), with negative resection margins (P < 0.001), with well/moderately differentiated tumors (P < 0.001), and those with negative lymph nodal status (P < 0.001). In multivariate analysis, negative margins (P < 0.001), tumor differentiation (P < 0.001), and negative nodal status (P < 0.001), but not tumor diameter, were significant independent prognostic factors. In R0-resected patients, lymph node status (P < 0.001), but not tumor diameter, histology, or differentiation, further predicted survival. The median survivals for R0-resected intrahepatic, perihilar, and distal tumors were 80, 30, and 25 months, respectively, and the 5-year survivals were 63%, 30%, and 27%, respectively. R0 resection remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R0 resection.
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            The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina.

            With the advent of genome-wide analyses, it is becoming evident that a large number of noncoding RNAs (ncRNAs) are expressed in vertebrates. However, of the thousands of ncRNAs identified, the functions of relatively few have been established. In a screen for genes upregulated by taurine in developing retinal cells, we identified a gene that appears to be a ncRNA. Taurine Upregulated Gene 1 (TUG1) is a spliced, polyadenylated RNA that does not encode any open reading frame greater than 82 amino acids in its full-length, 6.7 kilobase (kb) RNA sequence. Analyses of Northern blots and in situ hybridization revealed that TUG1 is expressed in the developing retina and brain, as well as in adult tissues. In the newborn retina, knockdown of TUG1 with RNA interference (RNAi) resulted in malformed or nonexistent outer segments of transfected photoreceptors. Immunofluorescent staining and microarray analyses suggested that this loss of proper photoreceptor differentiation is a result of the disregulation of photoreceptor gene expression. A function for a newly identified ncRNA, TUG1, has been established. TUG1 is necessary for the proper formation of photoreceptors in the developing rodent retina.
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              P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression

              Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                12 September 2017
                22 July 2017
                : 8
                : 39
                : 65823-65835
                Affiliations
                1 Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
                2 Department of The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
                Author notes
                Correspondence to: Yunfu Cui, yfcui777@ 123456hotmail.com
                Article
                19502
                10.18632/oncotarget.19502
                5630375
                29029475
                40aa6e1e-2ed7-4cbf-aa1b-09de60504758
                Copyright: © 2017 Xu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 February 2017
                : 30 June 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                cholangiocarcinoma,lncrna,tug1,prognosis,emt
                Oncology & Radiotherapy
                cholangiocarcinoma, lncrna, tug1, prognosis, emt

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