MicroRNAs and cancer: From the bench to the clinicMicroRNAs in the Pathogenesis of Cancer
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
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2021, Seminars in Cancer BiologyCitation Excerpt :Croce and colleagues initially discovered the importance of miRNAs in human cancer development when they found that miR-15a/16−1 cluster was frequently deleted in chronic lymphocytic leukemia (CLL), and miR-15a/16−1 loss was directly linked to Bcl2 overexpression [9]. After the discovery, alterations of miRNA expression have been found in all kinds of human cancers [10–12]. Most miRNAs have been found to be downregulated in human cancer tissues compared to normal tissue counterparts, and to function as tumor suppressor-like miRNAs by directly targeting oncogenes; while only a small portion of miRNAs that are upregulated in cancer tissues and function as oncogene-like miRNAs by directly suppressing tumor suppressor genes [13–15].
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Financial support: Kimmel Foundation Translational Cancer Research Scholar Award.
Conflicts of interest: None.