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Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer

Oncogene volume 37, pages 5020–5036 (2018)Cite this article

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Abstract

Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81602071 and 81672896); Jiangsu Provincial Clinical Science and Technology Projects (Clinical Research Center, BL2012008); the Natural Science Foundation of Jiangsu Province for Youth (BK20161066); and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine, JX10231801). We thank CloudSeq Biotech, Inc. (Shanghai, China) for help with bioinformatics analyses.

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Authors and Affiliations

  1. Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People’s Republic of China

    Tong-peng Xu, Wen-yu Wang, Pei Ma, You Shuai, Kun Zhao & Yong-qian Shu

  2. Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China

    Yan-fen Wang

  3. CloudSeq Biotech Inc., Shanghai, People’s Republic of China

    Wei Li

  4. Department of Medical Laboratory, Nanjing Chest Hospital, No. 215 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People’s Republic of China

    Rui Xia

  5. Department of Oncology, Jining No.1 People’s Hospital, Jining City, Shandong Province, 272011, People’s Republic of China

    Wen-ming Chen

  6. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China

    Er-bao Zhang

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Xu, Tp., Wang, Wy., Ma, P. et al. Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer. Oncogene 37, 5020–5036 (2018). https://doi.org/10.1038/s41388-018-0308-y

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