MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF
| Autor: | Anjan K. Pradhan, Praveen Bhoopathi, Luni Emdad, Paul B. Fisher, Sarmistha Talukdar, Devanand Sarkar, Swadesh K. Das, Danielle Scheunemann, Webster K. Cavenee |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Ribonuclease III Nude Apoptosis DEAD-box RNA Helicases Mice mda-7/IL-24 Neoplasms 2.1 Biological and endogenous factors Genes Tumor Suppressor Aetiology skin and connective tissue diseases Cancer Multidisciplinary Tumor biology Prostate Cancer ROS Cell Differentiation Argonaute Biological Sciences Microphthalmia-associated transcription factor Tumor Suppressor Biotechnology Signal Transduction Urologic Diseases Down-Regulation Mice Nude Cell Line Cell Line Tumor microRNA Genetics Animals Humans Transcription factor Drosha miRNA Cell Proliferation MITF Microphthalmia-Associated Transcription Factor Cell growth Interleukins Prostatic Neoplasms DICER Xenograft Model Antitumor Assays MicroRNAs Genes Cancer cell biology.protein Cancer research Reactive Oxygen Species Dicer |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 116, iss 12 |
| Popis: | Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a multifunctional cytokine displaying broad-spectrum anticancer activity in vitro or in vivo in preclinical animal cancer models and in a phase 1/2 clinical trial in patients with advanced cancers. mda-7/IL-24 targets specific miRNAs, including miR-221 and miR-320, for down-regulation in a cancer-selective manner. We demonstrate that mda-7/IL-24, administered through a replication incompetent type 5 adenovirus (Ad.mda-7) or with His-MDA-7/IL-24 protein, down-regulates DICER, a critical regulator in miRNA processing. This effect is specific for mature miR-221, as it does not affect Pri-miR-221 expression, and the DICER protein, as no changes occur in other miRNA processing cofactors, including DROSHA, PASHA, or Argonaute. DICER is unchanged by Ad.mda-7/IL-24 in normal immortal prostate cells, whereas Ad.mda-7 down-regulates DICER in multiple cancer cells including glioblastoma multiforme and prostate, breast, lung, and liver carcinoma cells. MDA-7/IL-24 protein down-regulates DICER expression through canonical IL-20/IL-22 receptors. Gain- and loss-of-function studies confirm that overexpression of DICER rescues deregulation of miRNAs by mda-7/IL-24, partially rescuing cancer cells from mda-7/IL-24-mediated cell death. Stable overexpression of DICER in cancer cells impedes Ad.mda-7 or His-MDA-7/IL-24 inhibition of cell growth, colony formation, PARP cleavage, and apoptosis. In addition, stable overexpression of DICER renders cancer cells more resistant to Ad.mda-7 inhibition of primary and secondary tumor growth. MDA-7/IL-24-mediated regulation of DICER is reactive oxygen species-dependent and mediated by melanogenesis-associated transcription factor. Our research uncovers a distinct role of mda-7/IL-24 in the regulation of miRNA biogenesis through alteration of the MITF-DICER pathway. |
| Databáze: | OpenAIRE |
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