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      Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma

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          Abstract

          Hepatoblastoma is the most common liver tumor of early childhood, which is usually characterized by unusual hypervascularity. Recently, long non-coding RNAs (lncRNA) have emerged as gene regulators and prognostic markers in several cancers, including hepatoblastoma. We previously reveal that lnRNA-TUG1 is upregulated in hepatoblastoma specimens by microarray analysis. In this study, we aim to elucidate the biological and clinical significance of TUG1 upregulation in hepatoblastoma. We show that TUG1 is significantly upregulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. TUG1 knockdown inhibits tumor growth and angiogenesis in vivo, and decreases hepatoblastoma cell viability, proliferation, migration, and invasion in vitro. TUG1, miR-34a-5p, and VEGFA constitutes to a regulatory network, and participates in regulating hepatoblastoma cell function, tumor progression, and tumor angiogenesis. Overall, our findings indicate that TUG1 upregulation contributes to unusual hypervascularity of hepatoblastoma. TUG1 is a promising therapeutic target for aggressive, recurrent, or metastatic hepatoblastoma.

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          Most cited references18

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          Angiogenesis in life, disease and medicine.

          The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
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            VEGF as a Key Mediator of Angiogenesis in Cancer

            Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. It is the key mediator of angiogenesis (the formation of new blood vessels), and binds two VEGF receptors (VEGF receptor-1 and VEGF receptor-2), which are expressed on vascular endothelial cells. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is the key mediator of angiogenesis in cancer, in which it is up-regulated by oncogene expression, a variety of growth factors and also hypoxia. Angiogenesis is essential for cancer development and growth: before a tumor can grow beyond 1–2 mm, it requires blood vessels for nutrients and oxygen. The production of VEGF and other growth factors by the tumor results in the ‘angiogenic switch’, where new vasculature is formed in and around the tumor, allowing it to grow exponentially. Tumor vasculature formed under the influence of VEGF is structurally and functionally abnormal. Blood vessels are irregularly shaped, tortuous, have dead ends and are not organized into venules, arterioles and capillaries. They are also leaky and hemorrhagic, which leads to high interstitial pressure. These characteristics mean that tumor blood flow is suboptimal, resulting in hypoxia and further VEGF production. This central role of VEGF in the production of tumor vasculature makes it a rational target for anticancer therapy.
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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
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                June 2016
                30 June 2016
                1 June 2016
                : 7
                : 6
                : e2278
                Affiliations
                [1 ]Department of Pediatric Surgery, Children's Hospital of Fudan University , Shanghai, China
                [2 ]Shanghai Key Laboratory of Birth Defect , Shanghai, China
                [3 ]Key Laboratory of Neonatal Disease, Ministry of Health , Shanghai, China
                Author notes
                [* ]Department of Pediatric Surgery, Children's Hospital of Fudan University , 399 Wan Yuan Road, Shanghai 201102, China. Tel: +86 2164931007; Fax: +86 2164931901; E-mail: szheng@ 123456shmu.edu.cn or kuirand@ 123456fudan.edu.cn
                Article
                cddis2016143
                10.1038/cddis.2016.143
                5108331
                27362796
                d29139da-3b42-4aa9-82e6-678c9f84a3e9
                Copyright © 2016 The Author(s)

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 15 December 2015
                : 11 March 2016
                : 11 April 2016
                Categories
                Original Article

                Cell biology
                Cell biology

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