MiR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth

Mariateresa Fulciniti, Nicola Amodio, R. L. Bandi, Antonia Cagnetta, M. K. Samur, Chirag Acharya, R. Prabhala, Patrizia D'Aquila, Dina Bellizzi, Giuseppe Passarino, Sophia Adamia, Antonino Neri, Zachary R. Hunter, Steven P. Treon, K. Anderson, Pierfrancesco Tassone, Nikhil Munshi

Research output: Contribution to journalArticle

Abstract

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.

Original languageEnglish
Article numbere380
JournalBlood Cancer Journal
Volume6
Issue number1
DOIs
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Oncology
  • Hematology

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    Fulciniti, M., Amodio, N., Bandi, R. L., Cagnetta, A., Samur, M. K., Acharya, C., Prabhala, R., D'Aquila, P., Bellizzi, D., Passarino, G., Adamia, S., Neri, A., Hunter, Z. R., Treon, S. P., Anderson, K., Tassone, P., & Munshi, N. (2016). MiR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth. Blood Cancer Journal, 6(1), [e380]. https://doi.org/10.1038/bcj.2015.106