Extensive post-transcriptional regulation of microRNAs and its implications for cancer.

By J. Thomson, Martin A. Newman, J. Parker, Elizabeth Morin-Kensicki, T. Wright, Scott M. Hammond. Genes & Development, 2006

907 citations recorded by the source corpus.

MicroRNAs (miRNAs) are short, noncoding RNAs that post-transcriptionally regulate gene expression. While hundreds of mammalian miRNA genes have been identified, little is known about the pathways that regulate the production of active miRNA species. Here we show that a large fraction of miRNA genes are regulated post-transcriptionally. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are present at high levels but are not processed by the enzyme Drosha. An analysis of gene expression in primary tumors indicates that the widespread down-regulation of miRNAs observed in cancer is due to a failure at the Drosha processing step. These data uncover a novel regulatory step in miRNA function and provide a mechanism for miRNA down-regulation in cancer.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/59d08e7b6c829eca7750ede5e4f7b037847d3348

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Citations in the corpus

A mammalian microRNA expression atlas based on small RNA library sequencing. (2007, background): “Regulated processing of miRNA precursor transcripts has also been reported in the context of cell-type and stage-specific expression (Obernosterer et al., 2006; Thomson et al., 2006).”
Genomic profiling of microRNA and mRNA reveals deregulated microRNA expression in prostate cancer (2008, background): “A decrease in the abundance of mature microRNA may result from altered processing, as shown recently (26), which would lead to an indiscriminate lower expression of mature microRNAs.”
MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. (2007, background): “Dysregulated miRNA expression may occur via a number of mechanisms, such as gene copy gain or loss (4), germline mutation of precursor miRNA molecules (5), promoter methylation (6), or aberrant miRNA processing due to altered expression of miRNA biogenesis machinery (7).”
Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. (2008, background): “Although a number of miRNAs, including let-7, miR-138, and miR-31, are known to be controlled posttranscriptionally (Lee et al., 2008; Obernosterer et al., 2006; Suh et al., 2004; Thomson et al., 2006; Wulczyn et al., 2007), the regulatory mechanisms remain unknown.”
microRNAs in cancer (2013, background): “Despite the almost ubiquitous expression of primary let-7 precursor in normal and cancer cells, the mature miRNA is produced abundantly in normal cells only (101).”
Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression (2007, background): “ing step, which appears deficient in tumors (48).”
Widespread microRNA repression by Myc contributes to tumorigenesis (2008, background): “Evidence suggests that a block in the first step of miRNA processing may contribute to the reduced abundance of select miRNAs in cancer cell”
MicroRNAs in development and disease. (2011, background): “This was initially predicted due to the lack of correlation between the levels of mature miRNAs and their primary transcripts in various normal and cancer cells (610).”
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “…microRNA expression can be also modulated as a consequence of defects in the microRNA biogenesis machinery, as supported by changes in microRNA levels consequent an altered Drosha or Dicer activity in different tumour types (Merritt et al, 2008; Nakamura et al, 2007; Thomson et al, 2006).”
An overview of microRNAs (2015, background): “Interestingly, transcription of the let-7 host genes does not increase significantly[124].”
Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells (2007, background): “Two of the best studied miRNAs are lin-4 and let-7 , which are involved in early ( lin-4 ) and late ( let-7 ) developmental timin”
Roles for microRNAs in conferring robustness to biological processes. (2012, neutral): “…30 UTRs with more miRNA-binding sites (Stark et al., 2005); (2) miRNA expression increases and diversifies over the course of embryonic development (Thomson et al., 2006), as 30 UTRs are lengthened via alternative polyadenylation site choice (Ji et al., 2009); and (3) the diversity of the miRNA…”
Impaired microRNA processing enhances cellular transformation and tumorigenesis (2007, background): “Recent work has also shown that the global repression of miRNAs in human cancers does not coincide with reductions in the primary miRNA transcripts, suggesting that altered regulation of the miRNA processing machinery occurs in human cancer”