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      The lncRNA HOXA11-AS regulates Rab3D expression by sponging miR-125a-5p promoting metastasis of osteosarcoma

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          Abstract

          Objective: Many studies have shown that long non-coding RNAs (lncRNAs) are closely related to various cancers. This study aims to explore the roles of lncRNA HOXA11-AS in the development and progression of osteosarcoma (OS).

          Methods: The expression levels of HOXA11-AS and miR-125a-5p in tumor tissues and the adjacent tissues were detected by RT-PCR method. The proliferation, migration and invasion of MG-63 and KHOS cells were determined.

          Results: It was found that HOXA11-AS expression levels in OS tissues and OS cell lines were higher than those in OS adjacent tissues and normal human osteoblast cell lines. The higher expression level of HOXA11-AS was positively correlated with more severe clinical stage, distant metastasis and poor prognosis of OS. Inhibition of HOXA11-AS expression could reduce metastasis and invasion of OS cell lines. In addition, HOXA11-AS was found to be an endogenous inhibitor of miR-125a-5p, it down regulated the expression level of miR-125a-5p, and this process could promote the expression of Rab3D, the target gene of miR-125a-5p.

          Conclusion: Our study elucidated the role of a new HOXA11-AS/miR-125a-5p/Rab3D regulatory pathway in promoting OS metastasis.

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          Most cited references23

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          LncRNA HOXA11-AS Promotes Proliferation and Invasion of Gastric Cancer by Scaffolding the Chromatin Modification Factors PRC2, LSD1, and DNMT1.

          Ming Sun, Fengqi Nie, Yunfei Wang … (2016)
          Long noncoding RNAs (lncRNA) have been implicated in human cancer but their mechanisms of action are mainly undocumented. In this study, we investigated lncRNA alterations that contribute to gastric cancer through an analysis of The Cancer Genome Atlas RNA sequencing data and other publicly available microarray data. Here we report the gastric cancer-associated lncRNA HOXA11-AS as a key regulator of gastric cancer development and progression. Patients with high HOXA11-AS expression had a shorter survival and poorer prognosis. In vitro and in vivo assays of HOXA11-AS alterations revealed a complex integrated phenotype affecting cell growth, migration, invasion, and apoptosis. Strikingly, high-throughput sequencing analysis after HOXA11-AS silencing highlighted alterations in cell proliferation and cell-cell adhesion pathways. Mechanistically, EZH2 along with the histone demethylase LSD1 or DNMT1 were recruited by HOXA11-AS, which functioned as a scaffold. HOXA11-AS also functioned as a molecular sponge for miR-1297, antagonizing its ability to repress EZH2 protein translation. In addition, we found that E2F1 was involved in HOXA11-AS activation in gastric cancer cells. Taken together, our findings support a model in which the EZH2/HOXA11-AS/LSD1 complex and HOXA11-AS/miR-1297/EZH2 cross-talk serve as critical effectors in gastric cancer tumorigenesis and progression, suggesting new therapeutic directions in gastric cancer. Cancer Res; 76(21); 6299-310. ©2016 AACR.
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            Update on Survival in Osteosarcoma.

            Megan E Anderson (2016)
            Osteosarcoma is the most common primary bone malignancy in children. Treatment has evolved to include systemic chemotherapy and local control surgery. Although survival improved initially in a drastic fashion with this approach, recent decades have seen little to no further gains in this area. Limb salvage surgery evolved with effective chemotherapy and advances in imaging, and continues to improve in the recent era. This article serves as a review of survival in high-grade osteosarcoma: prognostic factors, advances in chemotherapy and surgery, late effects of chemotherapy and surgery in survivors, and future directions.
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              Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b.

              John W. Park, H. R. Bae, Ji Heon Noh … (2013)
              Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD(+) )-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G1 /S phase and to suppress growth. This treatment restored p21(WAF1/Cip1) , induced Beclin-1, and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the in vivo tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21(WAF1/Cip1) -dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2'-deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the clinical significance of these findings, mutations in the DNA binding domain of p53 and promoter methylation of miR-125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in the p53 gene and one patient showed hypermethylation of the miR-125b promoter region. Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21(WAF1/Cip1) by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (HEPATOLOGY 2013). Copyright © 2012 American Association for the Study of Liver Diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Manag Res
                Journal ID (iso-abbrev): Cancer Manag Res
                Journal ID (publisher-id): CMAR
                Journal ID (pmc): cancmanres
                Title: Cancer Management and Research
                Publisher: Dove
                ISSN (Electronic): 1179-1322
                Publication date (Electronic): 16 May 2019
                Publication date Collection: 2019
                Volume: 11
                Pages: 4505-4518
                Affiliations
                [1 ]Department of Orthopaedics, The First Hospital Of Anhui Medical University , Hefei, People’s Republic of China
                [2 ]Department of Orthopaedics, The Second Hospital Of Shanxi Medical University , Taiyuan, People’s Republic of China
                Author notes
                Correspondence: Yong HuDepartment of Orthopaedics, The First Hospital of Anhui Medical University , Hefei, Anhui230022, People’s Republic of ChinaTel +86 551 629 23607Email huyong18504@ 123456163.com
                Article
                Publisher ID: 196025
                DOI: 10.2147/CMAR.S196025
                PMC ID: 6529177
                PubMed ID: 31191012
                SO-VID: c3c155af-2692-474e-952f-a348f1595fa5
                Copyright © © 2019 Cao et al.
                License:

                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).

                History
                Date received : 26 November 2018
                Date accepted : 22 April 2019
                Page count
                Figures: 8, Tables: 2, References: 29, Pages: 14
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: osteosarcoma (os),long non-coding rnas (lncrnas),hoxa11-as,mir-125a-5p,rab3d
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: osteosarcoma (os), long non-coding rnas (lncrnas), hoxa11-as, mir-125a-5p, rab3d

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