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DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells

Akio Iio1, Takeshi Takagi, Kohei Miki

  • 1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu, Gifu 501-1193, Japan; Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya-cho, Kasugai, Aichi 480-0392, Japan.

Biochimica Et Biophysica Acta
|August 13, 2013
PubMed

Insights

DEAD-box RNA helicase 6 (DDX6) protein degrades NCR143/145 RNA, reducing tumor suppressor microRNA (miRNA) miR-143/145 expression in cancer cells. This mechanism explains miRNA dysregulation in malignancies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • RNA Biology

Background:

  • MicroRNA (miRNA) expression is frequently dysregulated in human cancers, impacting cell growth.
  • Tumor suppressor miRNAs, like miR-143/145, are often downregulated in cancer due to various genetic and epigenetic factors.
  • The precise mechanisms underlying miR-143/145 downregulation in cancer remain largely unelucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms responsible for the downregulation of miR-143/145 in human cancers.
  • To identify proteins that interact with and regulate the expression of the miR-143/145 host gene, NCR143/145.
  • To elucidate the role of DEAD-box RNA helicase 6 (DDX6) in the post-transcriptional regulation of miR-143/145.

Main Methods:

  • Utilized human gastric cancer cell line MKN45 and human monocytic cell line THP-1.
  • Investigated the expression and localization of DDX6 protein, particularly in processing bodies (P-bodies).
  • Assessed the impact of DDX6 on NCR143/145 RNA stability and mature miR-143/145 expression using treatments like lipopolysaccharide and cycloheximide.

Main Results:

  • DDX6 protein was found to be abundantly expressed and accumulated in P-bodies in MKN45 cells.
  • DDX6 was shown to preferentially destabilize non-coding NCR143/145 RNA, leading to reduced mature miR-143/145 expression.
  • Lipopolysaccharide treatment induced P-body assembly and decreased NCR143/145 and miR-143/145 levels, while cycloheximide treatment disrupted P-bodies and increased NCR143/145 stability and miR-143/145 expression.

Conclusions:

  • DDX6 plays a critical role in the post-transcriptional regulation of miR-143/145 expression by controlling NCR143/145 RNA stability within P-bodies.
  • This DDX6-mediated mechanism contributes to the downregulation of tumor suppressor miR-143/145 in cancer cells.
  • The findings provide novel insights into miRNA dysregulation in cancer and potential therapeutic targets.
Keywords:
5′-3′ exoribonuclease 17-methylguanosine7mGACTBAGO1AGO2AREAU-rich elementsActDArgonaute 1Argonaute 2CHXCRM1DAPIDCP1 decapping enzyme homolog ADCP1ADDX17DDX5DDX6DEAD-box RNA helicase 17DEAD-box RNA helicase 5DEAD-box RNA helicase 6EDC3GAPDHHIF1AIFN-βIPZIgGLMBLPSLipopolysaccharideNCNCR143/145NMDP-bodiesPVDFRACERIPARISCRN7SL1RNA 7SL cytoplasmic 1RNA-induced silencing complexesRNU6BTNF-αU22 snoRNA host geneU6 small nuclear B RNAUHGXRN1actinomycin Dbeta-actincycloheximidediamidino-2-phenylindoleenhancer of mRNA decapping 3 homologglyceraldehyde-3-phosphate dehydrogenaseheterogeneous nuclear ribonucleoproteinshnRNPshypoxia inducible factor 1 alpha subunitimmunoglobulin Gimportazoleimportin family nuclear export receptorinterferon-betaleptomycin BmiR-143miR-145miRNAmicroRNAmicroRNA precursorsmicroRNA-143microRNA-143/145 host non-coding RNA genemicroRNA-145negative controlnon-spliced NCR143/145nonsense-mediated mRNA decaynsNCR143/145polyvinylidene fluoridepre-miRNAspri-miRNAsprimary microRNA transcriptsprocessing bodiesr15-LOXradioimmunoprecipitation assayrapid amplification of cDNA endsreticulocyte 15-lipoxigenasetumor necrosis factor-alpha

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