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      Long Noncoding RNA NEAT1 Upregulates Survivin and Facilitates Gallbladder Cancer Progression by Sponging microRNA-335

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          Abstract

          Background

          Gallbladder cancer (GBC) is the most common cancer of the biliary tract, but molecularly targeted therapies are not available for GBC. Loss of microRNA (miR)-335 expression may be a useful predictor of clinical outcomes and the reversal of its loss of expression may be a useful treatment strategy for GBC. In this study, we investigated whether a long noncoding RNA, nuclear paraspeckle assembly transcript 1 ( NEAT1) sponges miR-335 in GBC cells.

          Materials and Methods

          Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were used to determine the expression of miR-335; NEAT1; survivin; and Ki67 in GBC cell lines (GBC-SD and SGC-996) and tissue samples from patients (n = 25). Cell Counting Kit-8, colony-formation, and Transwell migration and invasion assays were performed to measure cell proliferation, migration, and invasion. Bioinformatic analysis and dual-luciferase reporter assays were utilized to analyze correlativity.

          Results

          miR-335 overexpression resulted in inhibition of GBC cell proliferation and invasion. In addition, knockdown of NEAT1 resulted in downregulation of survivin expression. As NEAT1 competitively “sponges” miR-335, NEAT1 knockdown resulted in inhibited GBC cell proliferation and invasion in vitro and GBC tumor growth in vivo. Furthermore, NEAT1 was found to be upregulated in GBC samples, and its expression was inversely correlated with miR-335 levels, but positively correlated with survivin levels.

          Conclusion

          These findings indicate that NEAT1 promotes survivin expression by functioning as a competitive endogenous RNA for miR-335 in GBC cells; thus, we have identified a potential biomarker and target for GBC diagnosis and therapy.

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          Most cited references 26

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          Gene silencing by microRNAs: contributions of translational repression and mRNA decay.

          Despite their widespread roles as regulators of gene expression, important questions remain about target regulation by microRNAs. Animal microRNAs were originally thought to repress target translation, with little or no influence on mRNA abundance, whereas the reverse was thought to be true in plants. Now, however, it is clear that microRNAs can induce mRNA degradation in animals and, conversely, translational repression in plants. Recent studies have made important advances in elucidating the relative contributions of these two different modes of target regulation by microRNAs. They have also shed light on the specific mechanisms of target silencing, which, although it differs fundamentally between plants and animals, shares some common features between the two kingdoms.
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            Carcinoma of the gallbladder.

            Carcinoma of the gallbladder is the most common malignant tumour of the biliary tract and a particularly high incidence is observed in Chile, Japan, and northern India. The aetiology of this tumour is complex, but there is a strong association with gallstones. Owing to its non-specific symptoms, gallbladder carcinoma is generally diagnosed late in the disease course, but if a patient with gallstones experiences a sudden change of symptoms, then a cancer diagnosis should be considered. Treatment with radical or extended cholecystectomy is potentially curative, although these procedures are only possible in 10-30% of patients. There is no role for cytoreductive surgery in this disease. If a gallbladder carcinoma is discovered via pathological examination of tissue samples, then the patient should be examined further and should have radical surgery if the tumour is found to be T1b or beyond. Additional port-site excision is necessary if the patient has already had their gallbladder removed during laparoscopy; however, patients with an intact gallbladder who are suspected to have gallbladder carcinoma should not undergo laparoscopic cholecystectomy. Patients with advanced inoperable disease should receive palliative treatment; however, the role of chemotherapy and radiation in these patients needs further evaluation.
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              Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma

              Background Accumulating evidences indicate that non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as crucial regulators in osteosarcoma (OS). Previously, we reported that Rho associated coiled-coil containing protein kinase 1 (ROCK1), a metastatic-related gene was negatively regulated by microRNA-335-5p (miR-335-5p) and work as an oncogene in osteosarcoma. Whether any long non-coding RNAs participate in the upstream of miR-335-5p/ROCK1 axial remains unclear. Methods Expression of differentiation antagonizing non-protein coding RNA (DANCR) and miR-335-5p/miR-1972 in osteosarcoma tissues were determined by a qRT-PCR assay and an ISH assay. Osteosarcoma cells’ proliferation and migration/invasion ability changes were measured by a CCK-8/EDU assay and a transwell assay respectively. ROCK1 expression changes were checked by a qRT-PCR assay and a western blot assay. Targeted binding effects between miR-335-5p/miR-1972 and ROCK1 or DANCR were verified by a dual luciferase reporter assay and a RIP assay. In vivo experiments including a nude formation assay as well as a CT scan were applied to detect tumor growth and metastasis changes in animal level. Results In the present study, an elevated DNACR was found in osteosarcoma tissue specimens and in osteosarcoma cell lines, and the elevated DNACR was closely correlated with poor prognosis in clinical patients. Functional experiments illustrated that a depression of DANCR suppressed ROCK1-mediated proliferation and metastasis in osteosarcoma cells. The results of western blot assays and qRT-PCR assays revealed that DANCR regulated ROCK1 via crosstalk with miR-335-5p and miR-1972. Further cellular behavioral experiments demonstrated that DNACR promoted ROCK1-meidated proliferation and metastasis through decoying both miR-335-5p and miR-1972. Finally, the outcomes of in vivo animal models showed that DANCR promoted tumor growth and lung metastasis of osteosarcoma. Conclusions LncRNA DANCR work as an oncogene and promoted ROCK1-mediated proliferation and metastasis through acting as a competing endogenous RNA (ceRNA) in osteosarcoma. Electronic supplementary material The online version of this article (10.1186/s12943-018-0837-6) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OTT
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                20 March 2020
                2020
                : 13
                : 2357-2367
                Affiliations
                [1 ]Department of General Surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong 637000, People’s Republic of China
                [2 ]Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200092, People’s Republic of China
                [3 ]Department of Biliary II, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Military Medical University , Shanghai 200438, People’s Republic of China
                Author notes
                Correspondence: Yinghe Qiu Department of Biliary II, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Military Medical University , No. 225 Changhai Road, Yangpu District, Shanghai200438, People’s Republic of China Email qiuyinghe8@aliyun.com
                Jingdong Li Department of General Surgery, Affiliated Hospital of North Sichuan Medical College , No. 63, Wenhua Road, Shunqing District, Nanchong637000, People’s Republic of China Email lijingdong358@126.com
                [*]

                These authors contributed equally to this work

                Article
                236350
                10.2147/OTT.S236350
                7093099
                © 2020 Yang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, References: 33, Pages: 11
                Categories
                Original Research

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