miRNAs A NOVEL TARGET FOR ANTICANCER THERAPY

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ABOUT AUTHORS:
Ketan M. Parmar*, Ritesh N. Sharma
S.K.Patel College of Pharmaceutical Education & research,
Department of Pharmaceutical chemistry, GANPAT UNIVERSITY.
*brave_student_90@yahoo.com

ABSTRACT
With the development of technologies to look at the expression levels of hundreds of miRNAs at a time and the clear role of miRNAs in cancers, groups began looking at miRNAs profiles of different cancers,especially the circulating miRNAs. We intended to make sure whether circulating miRNAs could be a promising biomarker of human cancers. Method: We comprehensively searched the Cochrane Library, Medline and EMbase from 1966 to Nov 2009 for the following terms: (“miRNA” or “microRNA”) and (“tumor” or “carcinoma”) and (“plasma” or “serum” or “circulating”). Detailed information was extracted from studies that met the inclusion criteria: blood-based miRNAs in human cancers and studies published in the English literature. Results: The current review show that different researches use different measurement methods which might impact the results;Cancers treatment might have an effect on circulating miRNAs; some miRNAs are multi-faceted RNA; small sample size might produce selection bias. Furthermore, because of the lack of randomized controlled trials and the heterogeneous nature of the available data, no attempt was made to perform quantitativemeta-analyses.
In this review, based on those researches, circulating miRNAs are promising and difficulties for their future application for diagnosing human cancers.


REFERENCE ID: PHARMATUTOR-ART-1739

INTRODUCTION
microRNA(abbreviated miRNA) is a short ribonucleic acid(RNA) molecule found in eukaryotic cells. A microRNA molecule has very few nucleotides(an average of 22) compared with other RNAs.(1)

miRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts(mRNAs), usually resulting in translational repression or target degradation and gene silencing. The human genome may encode over 1000 miRNAs, which may target about 60% of mammalian genes and are abundant in many human cell types.(2)

miRNAs show very different characteristics between plants and metazoans. In plants, repressions on the transcriptional level usually require a perfect or near-perfect target match, while a mismatched target can lead to gene silencing at the translational level. In metazoans, on the other hand, miRNA complementarity typically encompasses the 5' bases 2-7 of the microRNA, the microRNA seed region, and one miRNA can target many different sites on the same mRNA or on many different mRNAs. Another difference is the location of target sites on mRNAs. In metazoans, the miRNA target sites are in the three prime untranslated regions(3'UTR) of the mRNA.(3)

The first miRNAs were characterized in the early 1990s. However, miRNAs were not recognized as a distinct class of biological regulators with conserved functions until the early 2000s. Since then, miRNA research has revealed multiple roles in negative regulation (transcript degradation and sequestering, translational suppression) and possible involvement in positive regulation (transcriptional and translational activation). By affecting gene regulation, miRNAs are likely to be involved in most biological processes. Different sets of expressed miRNAs are found in different cell types and tissues.(4)

Aberrant expression of miRNAs has been implicated in numerous disease states, and miRNA-based therapies are under investigation.(5)



(FIGURE 1 - The stem-loopsecondary structureof a pre-microRNA from Brassica oleracea.(source - Lynan-Lennon BiolRev CambPhilosSoc. 2009 Feb;84(1):55-71)

History(6)
MicroRNAs were discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda Feinbaum during a study of the gene lin-14 in C. elegans development. They found that LIN-14 protein abundance was regulated by a short RNA product encoded by the lin-4 gene. A 61-nucleotide precursor from the lin-4 gene matured to a 22-nucleotide RNA that contained sequences partially complementary to multiple sequences in the 3’ UTR of the lin-14 mRNA. This complementarity was both necessary and sufficient to inhibit the translation of the lin-14 mRNA into the LIN-14 protein. Retrospectively, the lin-4 small RNA was the first microRNA to be identified, though at the time, it was thought to be a nematode idiosyncrasy. Only in 2000 was a second RNA characterized: let-7, which repressed lin-41, lin-14, lin-28, lin-42, and daf-12 expression during developmental stage transitions in C. elegans. let-7 was soon found to be conserved in many species, indicating the existence of a wider phenomenon.

Nomenclature(7)
Under a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication of their discovery. The prefix "mir" is followed by a dash and a number, the latter often indicating order of naming. For example, mir-123 was named and likely discovered prior to mir-456. The uncapitalized "mir-" refers to the pre-miRNA, while a capitalized "miR-" refers to the mature form. miRNAs with nearly identical sequences except for one or two nucleotides are annotated with an additional lower case letter. For example, miR-123a would be closely related to miR-123b. Pre-miRNAs that lead to 100% identical mature miRNAs but that are located at different places in the genome are indicated with an additional dash-number suffix. For example, the pre-miRNAs hsa-mir-194-1 and hsa-mir-194-2 lead to an identical mature miRNA099(hsa-miR-194) but are located in different regions of the genome. Species of origin is designated with a three-letter prefix, e.g., hsa-miR-123 is a human (Homo sapiens) miRNA and oar-miR-123 is a sheep (Ovisaries) miRNA. Other common prefixes include 'v' for viral (miRNA encoded by a viral genome) and 'd' for DrosophilamiRNA (a fruit fly commonly studied in genetic research).

When two mature microRNAs originate from opposite arms of the same pre-miRNA, they are denoted with a -3p or -5p suffix. (In the past, this distinction was also made with 's' (sense) and 'as' (antisense)). When relative expression levels are known, an asterisk following the name indicates an miRNA expressed at low levels relative to the miRNA in the opposite arm of a hairpin. For example, miR-123 and miR-123 would share a pre-miRNA hairpin, but more miR-123 would be found in the cell.

Mechanisms of miRNA-mediated repression
The mature strand of the miRNA is incorporated into a complex of ribonucleotide protein to form the miRNP , also called the miRNA – induced silencing complex (miRISC). The primary protein in this complex are members of the argonate (AGO)family,each of which possesses repressive capabilities.Mammals have four AGO protein (AGO1 – AGO4)of which only AGO2 has the potential to cleva target sequences due to its RNaseH-like domain (Peters and Meister 2007).

The mature miRNA is used as a guide in the miRNP to recognize its target mRNA, to which it may be complementary with different degrees. In plants , miRNAs exibit a near – perfest match to target,thereby triggering an RNAi – like mechanism that result in cleavage of target mRNAs.


(FIGURE 2 - Mechanisms of miRNA-mediated post-transcriptional regulation (Source –www.ambion.com)

Biogenesises(8)
The majority of the characterized miRNA genes are intergenic or oriented antisense to neighboring genes and are therefore suspected to be transcribed as independent units.However, in some cases a microRNA gene is transcribed together with its host gene; this provides a mean for coupled regulation of miRNA and protein-coding gene.As much as 40% of miRNA genes may lie in the introns of protein and non-protein coding genes or even in exons of long nonprotein-coding transcripts. These are usually, though not exclusively, found in a sense orientation, and thus usually are regulated together with their host genes .Other miRNA genes showing a common promoter include the 42-48% of all miRNAs originating from polycistronic units containing multiple discrete loops from which mature miRNAs are processed, although this does not necessarily mean the mature miRNAs of a family will be homologous in structure and function.


(FIGURE 3 – Biogenesis of  miRNAs ( Source - Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ (January 2006)

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