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广东快乐十分技巧任3:MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF
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MicroRNAs (miRNAs) are indispensable regulators of normal development and mediators of diverse diseases, including cancer, and cardiovascular and neurodegenerative diseases. As a consequence, the biogenesis of miRNAs is a critical determinant in disease etiology and pathogenesis. Cytoplasmic processing by DICER and downstream modifications of miRNAs are crucial regulators of miRNA biogenesis. mda-7/IL-24, a cancer-selective apoptosis-inducing cytokine, specifically downregulates expression of DICER, thereby deregulating miRNA expression. A link among mda-7/IL-24, DICER, and reactive oxygen species in cancer cells is described that might be exploited to produce enhanced and effective therapies for cancer. Accordingly, targeting this pathway uncovers exceptional opportunities to potentially eradicate cancer. This study demonstrates that mda-7/IL-24 effectively downregulates a miRNA processing protein and highlights the importance of the mda-7/IL-24-MITF-DICER-miRNA axis in cancer.
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.
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Author contributions: A.K.P., S.K.D., L.E., and P.B.F. designed research; A.K.P., P.B., S.T., and D. Scheunemann performed research; A.K.P., D. Sarkar, W.K.C., S.K.D., L.E., and P.B.F. analyzed data; and A.K.P., S.K.D., L.E., and P.B.F. wrote the paper.
Reviewers: H.E.G., Nebraska Medical Center; and P.T., Johns Hokins.
Conflict of interest statement: W.K.C. and P.B.F. are cofounders of InterLeukin Combinatorial Therapies, Inc. (ILCT). W.K.C., P.B.F., and Virginia Commonwealth University own stock in ILCT. L.E. is the principal investigator of a sponsored research agreement provided by ILCT to Virginia Commonwealth University. The other authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819869116/-/DCSupplemental.
Published under the PNAS license.