Elsevier

Seminars in Oncology

Volume 38, Issue 6, December 2011, Pages 724-733
Seminars in Oncology

MicroRNAs and cancer: From the bench to the clinic
MicroRNAs in the Pathogenesis of Cancer

https://doi.org/10.1053/j.seminoncol.2011.08.006Get rights and content

MicroRNAs (miRs) are small (19–25 nucleotides) non–protein-coding RNAs involved in development, differentiation, and aging; they act by inducing messenger RNA (mRNA) silencing through degradation, and post-transcriptional or decoy activity. miR profiles of human solid and hematologic malignancies have highlighted their potential value as tumor markers in cancer patient management. Different experimental lines of evidence have confirmed that deregulation of miRs not only results as consequence of cancer progression but also directly promotes tumor initiation and progression in a cause–effect manner. These findings reveal a potential and appealing role for miRs as cancer therapeutic targets. This review focuses on the causes and consequences of miR deregulation in carcinogenesis and tumor progression. The work aims at providing the molecular bases for the understanding of the potential role of miRs in the translational and clinical setting.

Section snippets

MicroRNAs and Genomic Instability

Genomic instability is a key element in tumor initiation and progression; at least three different mechanisms can be responsible for genomic instability: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype. These mechanisms often act separately and are associated with tumors of different clinical–pathological features.8 Genomic instability induces a feed-forward loop that allows cells to acquire several characteristics that provide them with a

Epigenomics

Epigenetic silencing of structurally normal genes by aberrant DNA methylation or histone deacetylation can be considered a fundamental step in the acquisition of genetic instability.

miR genes as well as other protein-coding genes are affected by hyper- or hypomethylation of CpG islands harbored in their promoters. Lujambo et al compared miR expression in methyltransferase (DNMT1 and DNMT3a)-deficient and WT colon cancer cell lines.33 Six percent of the 320 analyzed miRs were upregulated in the

Proliferation, Differentiation, and Apoptosis

Deregulation of cell proliferation, differentiation, and apoptosis represents one of the main hallmarks of cancer initiation and progression. miRs take part in this process by controlling different steps and affecting integrated pathways involved in carcinogenesis. miR-15 and miR-16 represent clear examples being located at a crossway between apoptosis and cell cycle control. As mentioned earlier, miR-15a and miR–16–1, whose loci are deleted in more than half of cases of B-CLL and in advanced

Angiogenesis

During tumor progression, the “angiogenic switch” is a key step for the expansion of a tumor mass. This switch is primarily activated when a growing tumor mass surpasses the maximal volume that can be sustained by diffusion of oxygen and nutrients.59 Low oxygen tension in large burden tumors induces cancer cells to overexpress the hypoxia-inducible transcription factor 1 (HIF-1). This transcription factor binds to hypoxia-response elements (HREs) located upstream of target genes, and activates

Invasion and Metastasis

The metastatic process includes complex and multiple steps: cell motility, tissue invasion, intravasation, translocation through the blood and lymph system, extravasation, and initial microscopic growths at a new site.72 Cancer-associated miRs harbor anti- or pro-metastatic properties by regulating genes involved in metastasis prevention or promotion, respectively.

One of the most important and controversial miRs involved in metastasis control is miR-10b. Iorio et al initially reported that

Conclusions

miRs have been implicated in several steps of human carcinogenesis. Growing evidence is proving that miRs can modulate crucial pathways affecting tumor initiation and progression. miRs are now under evaluation in prospective clinical trials to elicit their potential as diagnostic and prognostic markers, predictors of chemotherapy response, and potential therapeutic targets. miR-based research has received a huge amount of funding over the last several years; this led to interesting and

References (86)

  • M. Garofalo et al.

    miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation

    Cancer Cell

    (2009)
  • W.J. Yang et al.

    Dicer is required for embryonic angiogenesis during mouse development

    J Biol Chem

    (2005)
  • S. Wang et al.

    The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis

    Dev Cell

    (2008)
  • J.E. Fish et al.

    miR-126 regulates angiogenic signaling and vascular integrity

    Dev Cell

    (2008)
  • T. Wurdinger et al.

    miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells

    Cancer Cell

    (2008)
  • Y. Chen et al.

    The homeobox gene GAX activates p21WAF1/CIP1 expression in vascular endothelial cells through direct interaction with upstream AT-rich sequences

    J Biol Chem

    (2007)
  • L. Poliseno et al.

    MicroRNAs modulate the angiogenic properties of HUVECs

    Blood

    (2006)
  • Y. Tian et al.

    MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines

    J Biol Chem

    (2010)
  • C.H. Moriarty et al.

    miR-10b targets Tiam1: implications for Rac activation and carcinoma migration

    J Biol Chem

    (2010)
  • F. Meng et al.

    MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer

    Gastroenterology

    (2007)
  • P.M. Voorhoeve et al.

    A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors

    Cell

    (2006)
  • G. Martello et al.

    A MicroRNA targeting dicer for metastasis control

    Cell

    (2010)
  • R. Feng et al.

    miR-126 functions as a tumour suppressor in human gastric cancer

    Cancer Lett

    (2010)
  • J. Lu et al.

    MicroRNA expression profiles classify human cancers

    Nature

    (2005)
  • N. Rosenfeld et al.

    MicroRNAs accurately identify cancer tissue origin

    Nat Biotechnol

    (2008)
  • A.J. Schetter et al.

    MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma

    JAMA

    (2008)
  • G.A. Calin et al.

    A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia

    N Engl J Med

    (2005)
  • J.R. Pollack et al.

    Characterizing the physical genome

    Nat Genet

    (2002)
  • A. Aguilera et al.

    Genome instability: a mechanistic view of its causes and consequences

    Nat Rev Genet

    (2008)
  • G.A. Calin et al.

    Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

    Proc Natl Acad Sci U S A

    (2004)
  • C. Sevignani et al.

    MicroRNA genes are frequently located near mouse cancer susceptibility loci

    Proc Natl Acad Sci U S A

    (2007)
  • K. Huppi et al.

    The identification of microRNAs in a genomically unstable region of human chromosome 8q24

    Mol Cancer Res

    (2008)
  • D. Bonci et al.

    The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities

    Nat Med

    (2008)
  • J. Ding et al.

    Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA

    Nat Cell. Biol

    (2010)
  • L. Ma et al.

    miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis

    Nat Cell Biol

    (2010)
  • A. Lal et al.

    miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells

    Nat Struct Mol Biol

    (2009)
  • M.E. Crosby et al.

    MicroRNA regulation of DNA repair gene expression in hypoxic stress

    Cancer Res

    (2009)
  • E.H. Blackburn

    Structure and function of telomeres

    Nature

    (1991)
  • R. Benetti et al.

    A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases

    Nat Struct Mol Biol

    (2008)
  • C. Kanellopoulou et al.

    Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing

    Genes Dev

    (2005)
  • E.P. Murchison et al.

    Characterization of Dicer-deficient murine embryonic stem cells

    Proc Natl Acad Sci U S A

    (2005)
  • A. de la Chapelle

    Microsatellite instability

    N Engl J Med

    (2003)
  • L.A. Loeb

    A mutator phenotype in cancer

    Cancer Res

    (2001)
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    Financial support: Kimmel Foundation Translational Cancer Research Scholar Award.

    Conflicts of interest: None.

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