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The Lncrna NEAT1 Activates Wnt/Β-Catenin Signaling and Promotes Colorectal Cancer Progression Via Interacting with DDX5

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The Lncrna NEAT1 Activates Wnt/Β-Catenin Signaling and Promotes Colorectal Cancer Progression Via Interacting with DDX5 Zhang et al. Journal of Hematology & Oncology (2018) 11:113 https://doi.org/10.1186/s13045-018-0656-7 RESEARCH Open Access The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5 Meng Zhang1,2,3†, Weiwei Weng1,3,4†, Qiongyan Zhang1,3,4, Yong Wu3,4, Shujuan Ni1,3,4, Cong Tan1,3,4, Midie Xu1,3,4, Hui Sun1,3,4, Chenchen Liu4,6, Ping Wei1,3,4,5,6* and Xiang Du1,2,3,4,5* Abstract Background: The long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been reported to be overexpressed in colorectal cancer (CRC). However, its underlying mechanisms in the progression of CRC have not been well studied. Methods: To investigate the clinical significance of NEAT1, we analyzed its expression levels in a publicly available dataset and in 71 CRC samples from Fudan University Shanghai Cancer Center. Functional assays, including the CCK8, EdU, colony formation, wound healing, and Transwell assays, were used to determine the oncogenic role of NEAT1 in human CRC progression. Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and Dual-Luciferase Reporter Assays were used to determine the mechanism of NEAT1 in CRC progression. Animal experiments were used to determine the role of NEAT1 in CRC tumorigenicity and metastasis in vivo. Results: NEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues. AlteredNEAT1expressionledtomarkedchangesinproliferation, migration, and invasion of CRC cells both in vitro and in vivo. Mechanistically, we found that NEAT1 directly bound to theDDX5protein,regulatedits stability, and sequentially activated Wnt signaling. Our study showed that NEAT1 indirectly activated the Wnt/β-catenin signaling pathway via DDX5 and fulfilled its oncogenic functions in a DDX5-mediated manner. Clinically, concomitant NEAT1 and DDX5 protein levels negatively correlated with the overall survival and disease-free survival of CRC patients. Conclusions: Our findings indicated that NEAT1 activated Wnt signaling to promote colorectal cancer progression and metastasis. The NEAT1/DDX5/Wnt/β-catenin axis could be a potential therapeutic target of pharmacological strategies. Keywords: NEAT1, lncRNA, DDX5, β-Catenin, Colorectal cancer Background alterations and their underlying mechanisms in CRC Colorectal cancer (CRC) is the third most common can- should be explored more intensively to discover prog- cer and the third leading cause of cancer-related death nostic biomarkers and therapeutic targets for CRC. in men and women in the USA, accounting for Long noncoding RNAs (lncRNAs) are defined as RNA one-tenth of all cancer-related deaths in women and polymerase II transcripts longer than 200 nucleotides in men [1]. Treatment regimens for advanced CRC involve length that lack a significant protein-coding capacity [3, combination chemotherapies, which are toxic and largely 4]. Over the past two decades, the biogenesis and func- ineffective but have remained the backbone of treatment tional mechanisms of miRNAs have been extensively over the past decade [2]. Hence, genetic and epigenetic elucidated. Nevertheless, the roles of lncRNAs remain unclear. lncRNAs have a great biological significance in the occurrence and progression of cancers because they * Correspondence: [email protected]; [email protected] † can interact with cancer stem cells and then affect can- Meng Zhang and Weiwei Weng contributed equally to this work. 1Department of Pathology, Fudan University Shanghai Cancer Center, cer metastasis and recurrence [5]. lncRNAs potentially Shanghai 200032, China act through various mechanisms that may be related to a Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. Journal of Hematology & Oncology (2018) 11:113 Page 2 of 13 wide range of subcellular localizations, expression levels, prior to surgical resection at Fudan University Shanghai and stability in mammalian cells [6, 7]. As expected, in- Cancer Center (FDUSCC) between 2008 and 2009. creasing evidence suggests that many lncRNAs fulfill This study was approved by the institutional review their functions through specific interactions with other board of Shanghai Cancer Center. The median follow-up cellular factors (proteins, DNA, and other RNA mole- time was 80 months, and the longest follow-up was cules). Hence, finding lncRNA interacting partners is 87 months. considered a strategy to gain insights into their molecu- lar mechanisms [6]. Transient and stable transfections Many lncRNAs potentially act as scaffolds to bring NEAT1 siRNAs (si1: sense 5’-GACCGUGGUUUGUU together different proteins or bridge protein complexes ACUAUdTdT-3′,antisense5′-AUAGUAACAAACCA via their protein interaction capabilities [8]. For example, CGGUCdTdT-3′;si2:sense5′-GUUGGUCAUUCCUA NEAT1 and MALAT1 bind multiple proteins localized AAUCUTT-3′,antisense5′-AGAUUUAGGAAUGACC to paraspeckles and nuclear speckles, respectively [9– AACTT-3′), si-DDX5 (sense: 5′-GCAAGUAGCUGCUG 11]. The lncRNA NEAT1 is abnormally upregulated in AAUAUUU-3′,antisense:5′-pAUAUUCAGCAGCUA somatic malignancies and has been found to promote CUUGCUU-3′), and a scramble siRNA were purchased tumor growth in CRC [12–14]. Nevertheless, elucidating from GenePharma (Shanghai, China). ShNEAT1 lenti- the molecular mechanisms underlying the oncogenic viruses (5′-GACCGUGGUUUGUUACUAU-3′)andshNC functions of NEAT1 requires further effort. Identifying (representing the sh-negative control, 5′-UUCUCCGAACG the upstream and downstream targets of NEAT1 will UGUCACGU-3′) were generated by Sbo-Bio (Shanghai, elucidate its critical role in tumor progression. China). Transient transfection of pc3.1-NEAT1, pc3.1 In most cases, inappropriate activation of the proto- (control vector), or siRNA was performed using Lipofecta- oncoprotein β-catenin is thought to induce tumor for- mine 3000 (Invitrogen, CA, USA) according to the manu- mation. Mutations of the tumor suppressors APC and facturer’s instructions. To establish stable cell lines, axin, which are found in many colorectal tumors, pre- shNEAT1 lentiviruses were transduced into HCT116 and vent β-catenin degradation, and phosphorylation [15, SW1116 cells with polybrene (5 μg/mL; Sigma-Aldrich, 16]. All of these mutations cause both nuclear accumula- MO, USA). Then, the cells were selected with 0.5 μg/mL tion of β-catenin, thereby contributing to its ability to of puromycin for 14 days. The transfection efficiencies bind T cell transcription factors, and upregulation of were verified by RT-qPCR and western blotting. proto-oncogenes, such as c-myc, Axin2, and cyclin D1 [17–19]. Recently, decreased NEAT1 expression was re- Animal experiments ported to inhibit Wnt/β-catenin signaling pathway activ- This study complied with the Animal Care guidelines ity. However, the molecular mechanisms underlying this of FDUSCC. Male BALB/c nude mice (6 weeks old) phenomenon are unknown. were housed under specific pathogen-free conditions. In this study, we revealed the key functions of NEAT1 HCT116-shNC and HCT116-shNEAT1 cells were in the proliferation, migration, and invasion of CRC cells injected either subcutaneously (n =4,5×106/mouse) or both in vitro and in vivo. Notably, we provided evidence into the tail vein (n =4,2×106/mouse). The mice were that NEAT1 directly bound to DDX5 and enhanced its sacrificed after 4–6 weeks. The tumors and lungs of protein stability. NEAT1 activated the transcriptional ac- the mice were removed, fixed in 10% formalin, and tivity of β-catenin to promote CRC tumor progression in stored at − 80 °C for the subsequent analyses. Each a DDX5-mediated manner. Clinically, NEAT1 expression animal experiment was performed in triplicate. was elevated in CRC tissues and positively correlated with DDX5 expression. Taken together, these results Western blotting suggest that NEAT1 and DDX5 in combination may be The standard western blotting assay was performed as valuable prognostic predictors for CRC. Thus, the previously described [20]. The specific primary anti- NEAT1/DDX5/β-catenin axis appears to be a promising bodies are listed in Additional file 2: Table S1. target for CRC therapy. RNA pull-down, mass spectrometry, and RNA Methods immunoprecipitation assays Please find the complete Materials and Methods in RNA pull-down was performed using the Magnetic Additional file 1. RNA-Protein Pull-Down kit (Pierce, MA, USA) in accord- ance with the manufacturer’s instructions. The protein CRC patient information bands on the gel were silver-stained. Bands of interest Fresh samples were obtained from 71 newly diagnosed were identified by mass spectrometry (MS) and confirmed CRC patients who underwent no preoperative therapy by western blotting. RNA immunoprecipitation (RIP) was Zhang et al. Journal of Hematology & Oncology (2018) 11:113 Page 3 of 13 performed using the Magna RIP RNA-Binding Protein parameters were compared using the χ2
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