Review
Roles of small RNAs in tumor formation

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MicroRNAs (miRNAs) are small noncoding RNAs that act as post-transcriptional repressors of gene expression in organisms ranging from plants to humans. A widespread role for miRNAs in diverse molecular processes driving the initiation and progression of various tumor types has recently been described. Here, we discuss the etiology of the aberrant expression of miRNAs in human cancers and their role in tumor metastasis, which might define miRNAs as oncogenes or tumor suppressors. Moreover, we highlight the genomic/epigenetic alterations and transcriptional/post-transcriptional mechanisms associated with the misexpression of miRNAs in cancer. A better understanding of miRNA biology might ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies against cancer.

Section snippets

microRNAs

Over the past decade, in different species and in a range of tissues, several classes of small regulatory RNAs have been identified including miRNAs, small (18–25 nucleotides (nt) in length), noncoding, single-stranded RNAs. MiRNAs negatively regulate gene expression, either by translational inhibition or exonucleolytic mRNA decay, targeted through imperfect complementarity between the miRNA and the 3′ untranslated region (3′UTR) of the mRNA [1]. Depending on the targeted mRNAs, both mechanisms

MiRNA biogenesis: from nucleus to cytoplasm

Since their discovery (Box 1), hundreds of miRNAs have been identified and, at present, the human miRNA database contains 721 miRNAs or approximately 2–3% of the total number of genes in the human genome (Box 2). MiRNAs are produced through a multistep process, including two distinct biogenetic pathways (Figure 1) [extensively reviewed in 4]. During the miRNA maturation processes, transcriptional and post-transcriptional levels are strictly regulated, ensuring precise production. Disruptions in

MiRNA expression in cancer

Although initially identified in B-cell leukemia [5], alterations in the expression of miRNAs are now considered a common characteristic of all human tumors. Compared with normal tissue of the same type, most tumors display a distinct miRNA expression signature (Table 1). In 2006, Lu and collaborators demonstrated that expression profiles of miRNAs could accurately classify human cancers on the basis of their embryonic lineage and differentiation states [6]: tumors of endodermal origin, such as

Causes of abnormal miRNA expression in cancer

Because aberrant miRNA levels are strongly associated with disease, the precise control of miRNA levels is essential for maintaining normal cellular homeostasis. In the following section, we review the major mechanisms involved in miRNA dysregulation in cancer (Figure 2).

Concluding remarks

The rapidly progressing field of small regulatory RNAs continues to reveal the diversity and complexity of the RNA world. However, despite remarkable recent progress, the connection between cancer and miRNAs remains incompletely understood and many important questions remain. First, genome-wide analyses for alterations in miRNA genes or for copy number alterations in various human tumors are needed to identify all of the putative tumor suppressor and oncogenic miRNAs. At the same time, more

Acknowledgements

We sincerely thank Dr Kenneth Nephew for the critical reading of the manuscript and Michela Garofalo and Flavia Pichiorri for suggestions.

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