Adenosine deaminase acting on RNA (ADAR) converts adenosine to inosine specifically in dsRNA (A- to-I RNA editing). Our pioneering studies demonstrated the involvement of A-to-I RNA editing in the control of miRNA biogenesis and function. We recently found that loading of the EBV (Epstein-Barr-virus) miRNA miR- BART6 onto a functional RISC complex is inhibited by A-to-I editing of its primary transcript (pri-miR-BART6) by ADAR1. Moreover, four binding sites of miR-BART6-5p were identified within the human Dicer mRNA 3'UTR, revealing a unique strategy of EBV to manipulate the host RNAi mechanism. Tumor metastasis is the most common cause of death in patients with cancer, including breast cancer. The Epithelial-to-Mesenchymal Transition (EMT) plays an important role in metastasis. Snail, Slug, and Twist have been identified as major regulators of EMT. In addition to these conventional transcription factor proteins, miRNAs have emerged as new key factors that control EMT. Recent studies suggest that two miRNAs, miR- 103 and miR-107, promote the EMT by silencing Dicer and thereby repressing global synthesis of miRNAs, including a major EMT-inhibitory miRNA, miR-200. EBV is one of the most common human viruses, infecting more than 90% of the world's population, and association of latent EBV infection with a variety of human cancers such as Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma is well established. EBV is frequently detected in human breast cancer specimens. Furthermore, more frequent detection of EBV in higher grade (metastatic) breast cancers has been reported. However, very little is known about the relevance of EBV to breast cancer causation and in particular metastasis. Recent studies by us indicate a previously unexplored possibility that EBV infection may play an important role in progression of breast tumors to metastasis. We hypothesize that miR-BART6-5p and its editing by ADAR1 control EMT through targeting Dicer, and contribute to metastasis of EBV positive breast cancer. Information obtained through this research proposal may lead to a new intervention for the prevention or therapeutic treatment of metastatic breast cancer. The long-term goal of this project is to better understand functions of EBV miR-BART6 in metastasis and the control mechanism mediated via A-to-I RNA editing. Specifically, we will determine: 1) the function of miR-BART6 RNAs in promotion of EMT in human breast cancer cell lines;2) the significance of RNA editing in the EMT promoting function of miR-BART6;3) the role of miR-BART6 in vivo in breast cancer metastasis using an orthotopic tumor implantation mouse model;and 4) the miR-BART6 and ADAR1 expression levels in human breast tumor specimens and their relevance to metastatic progression.

Public Health Relevance

Our proposed research will reveal new and critical information on a mechanism that regulates metastasis of human breast cancer by an Epstein-Barr Virus (EBV) microRNA. EBV is ubiquitous, infecting more than 90% of the world's population, and the latently infected EBV is associated with a variety of human cancers such as Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma. However, the role of EBV microRNA in the metastasis of breast cancer has never been investigated before. Information obtained through this research proposal is essential for the future development of a new intervention for prevention or treatment of breast cancer metastasis caused by EBV.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Daschner, Phillip J
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Wistar Institute
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Nishikura, Kazuko (2017) Oesophageal cancer: RNA editing of SLC22A3 mRNAs: causative relevance to familial ESCC? Nat Rev Gastroenterol Hepatol 14:569-570
Sakurai, Masayuki; Shiromoto, Yusuke; Ota, Hiromitsu et al. (2017) ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay. Nat Struct Mol Biol 24:534-543
Tan, Meng How; Li, Qin; Shanmugam, Raghuvaran et al. (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254
Song, Chunzi; Sakurai, Masayuki; Shiromoto, Yusuke et al. (2016) Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases. Genes (Basel) 7:
Miyake, Kotaro; Ohta, Toshio; Nakayama, Hisako et al. (2016) CAPS1 RNA Editing Promotes Dense Core Vesicle Exocytosis. Cell Rep 17:2004-2014
Nishikura, Kazuko (2016) A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 17:83-96
Gumireddy, Kiranmai; Li, Anping; Kossenkov, Andrew V et al. (2016) The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis. Nat Commun 7:10715
Watanabe, Yoshihisa; Yoshimoto, Kanji; Tatebe, Harutsugu et al. (2014) Enhancement of alcohol drinking in mice depends on alterations in RNA editing of serotonin 2C receptors. Int J Neuropsychopharmacol 17:739-51