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CRTC1-MAML2 fusion-induced lncRNA LINC00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells

Oncogene volume 37, pages 1885–1895 (2018)Cite this article

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Abstract

Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.

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Acknowledgements

This work is supported by the NIH National Institute of Dental and Craniofacial Research (R01DE023641) and the NIH National Cancer Institute (R21CA187730).

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

    Zirong Chen, Wei Ni & Lizi Wu

  2. UF Health Cancer Center, University of Florida, Gainesville, FL, USA

    Zirong Chen, Wei Ni, Jianrong Lu, Frederic J. Kaye & Lizi Wu

  3. Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Shuibin Lin

  4. Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA

    Jian-Liang Li

  5. UF Genetics Institute, University of Florida, Gainesville, FL, USA

    Wei Ni & Lizi Wu

  6. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA

    Ruifeng Guo

  7. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA

    Jianrong Lu

  8. Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA

    Frederic J. Kaye

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Chen, Z., Lin, S., Li, JL. et al. CRTC1-MAML2 fusion-induced lncRNA LINC00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells. Oncogene 37, 1885–1895 (2018). https://doi.org/10.1038/s41388-017-0104-0

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