A study of microRNAs in silico and in vivo: diagnostic and therapeutic applications in cancer - PubMed (original) (raw)

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A study of microRNAs in silico and in vivo: diagnostic and therapeutic applications in cancer

Scott A Waldman et al. FEBS J. 2009 Apr.

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Abstract

There is emerging evidence of the production in human tumors of abnormal levels of microRNAs (miRNAs), which have been assigned oncogenic and/or tumor-suppressor functions. While some miRNAs commonly exhibit altered amounts across tumors, more often, different tumor types produce unique patterns of miRNAs, related to their tissue of origin. The role of miRNAs in tumorigenesis underscores their value as mechanism-based therapeutic targets in cancer. Similarly, unique patterns of altered levels of miRNA production provide fingerprints that may serve as molecular biomarkers for tumor diagnosis, classification, prognosis of disease-specific outcomes and prediction of therapeutic responses.

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Figures

Figure 1

Figure 1. MicroRNA generation and gene regulation [9]

Mature microRNAs of about 22 nucleotides originate from primary microRNA (pri-microRNA) transcripts. Nuclear pri-microRNAs of hundreds to thousands of base pairs are converted into stem-loop precursors (pre-microRNA) of about 70 nucleotides by Drosha, an RNase III endonuclease, and Pasha, a homologue of the human DiGeorge syndrome critical region gene 8 (DGCR8). Pre-microRNAs undergo cytoplasmic translocation mediated by exportin 5 in conjunction with Ran-GTP and subsequently processed into RNA duplexes of about 22 nucleotides by Dicer, an RNase III enzyme, and Loqacious (Loqs), a double-stranded RNA-binding–domain protein that is a homologue of the HIV transactivating response RNA-binding protein (TRBP). The functional strand of the microRNA duplex guides the RNA-induced silencing complex (RISC) to the mRNA target for translational repression or degradation. Figure reproduced from (9).

Figure 2

Figure 2. MicroRNA oncogenes and tumor suppressors [26]

a. Normally, microRNA (miRNA) binding to target mRNA represses gene expression by blocking protein translation or inducing mRNA degradation, contributing to homeostasis of growth, proliferation, differentiation and apoptosis. b. Reduced miRNA levels, reflecting defects at any stage of mirRNA biogenesis (indicated by question marks), produce inappropriate expression of target oncoproteins (purple squares). The resulting defects in homeostasis increase proliferation, invasiveness or angiogenesis or decrease levels o f apoptosis or differentiation, potentiating tumor formation. c. Conversely, overexpression of an oncogenic miRNA eliminates the expression of tumor-suppressor genes (pink), leading to cancer progression. Increased levels of mature miRNA could reflect amplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of the miRNA (indicated by question marks). ORF, open reading frame. Figure reproduced from (26).

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