miRNAs as Biomarkers in Cancer

Role of miRNAs in oncogenesis has been investigated. miRNAs can behave like oncogenes, which promote tumor growth, or tumor suppressors, which keep potentially malignant cells in check. miRNA activity is tissue-sensitive, meaning some miRNAs may be overexpressed, or “turned on” in some of the cancers while in others they are underexpressed, or “turned off.” Increased expression of miR- 21, an oncogene leads to increased human telomerase reverse transcriptase (hTERT) expression and increased telomerase activity causes cell immortalization - characteristic of cancer. Decreased expression of let-7, a tumor suppressor increases expression of oncogene RAS and induces cell proliferation - another feature of cancer.

miRNA genes are frequently located in cancer-associated regions of the genome, e.g. at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. They can act both as tumor suppressor genes and oncogenes. The classic paradigm in oncogenesis is the accumulation of mutations in the open reading frames of proteinencoding oncogenes and tumor suppressors. The identification of miRNAs that are important for development and cell homeostasis will likely change this paradigm of cancer. The determination of miRNA profiles as a new class of biomarkers has the potential to significantly improve diagnostic accuracy and prognostic information. The full complement of miRNAs in a genome may be extensively involved in cancer However, a small percentage of miRNA genes located in deleted regions had low levels of expression in cancer samples.

Several studies of miRNAs highlight a requirement for cell viability. Posttranscriptional silencing of target genes by miRNAs occurs either by targeting specific cleavage of homologous mRNAs, or by targeting specific inhibition of protein synthesis. A multisubunit protein complex termed ‘microprocessor’ is necessary and sufficient for processing miRNA precursor RNAs. Microprocessor contains Drosha, an RNase III endonuclease, and DGCR8, a gene deleted in DiGeorge syndrome. These findings link miRNA perturbation to cancer.

One cluster of miRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B cell lymphomas and the levels of the primary or mature miRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster has been shown to act with c-myc expression to accelerate tumor development in a mouse B cell lymphoma model. A set of five miRNAs, including the three most up-regulated ones (miR-221, -222, and -146), can distinguish unequivocally between papillary thyroid carcinoma and normal thyroid indicating their involvement in the pathogenesis of carcinoma. Marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer. Most of the studies indicate that miRNAs, can modulate tumor formation, and implicate mir-17-92 cluster as a potential human oncogene.

A cancer miRNA signature, composed of a large portion of overexpressed miRNAs, has been identified from a large-scale miRnome analysis of samples of several cancers. These miRNAs include some with well characterized cancer association, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155. A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes have been confirmed in experimental studies. These results indicate that miR- NAs are extensively involved in pathogenesis of solid cancers and support their function as either dominant or recessive cancer genes. Finding such a signature is important because it shows that many forms of cancer share common genetic pathways that become scrambled as cancer takes hold and spreads. The findings also pave the way for new approaches in diagnosis and treatment. miRNAs themselves may 1 day be used as therapeutics. If miRNAs that are lost are replaced and those that are overly abundant are blocked, it may be possible to prevent some of the very earliest changes that occur in the development of cancer.

Usefulness of miRNAs for the detection, diagnosis, prognosis, and possible treatment of human cancer will depend on carefully designed translational studies. In addition, it will require careful consideration of the best methods for sample collection, miRNA isolation, miRNA quantitation, and data analysis. To facilitate this, there is a need to gain a better understanding of specific miRNA characteristics, such as how targeting of multiple mRNAs by a single miRNA affects data interpretation in biomarker studies and the effect of miRNA isoforms on diagnostic utility. In the therapeutic area, targeting of the correct miRNA sites without affecting miRNA targets of similar sequence will be required.

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