MicroRNAs(Role In Cancer)

Introduction• MicroRNAs (miRNAs) are small non-coding RNAs of

approximately 22 nucleotides (nt) and act as post-transcriptional regulators of gene expression.

• This type of regulation was first described in Caenorhabditis elegans in 1993 and it has since been described in many other organisms.

• Today, more than 1,400 miRNAs have been described in humans, constituting 1 to 3% of the genes in the human genome

• It has been estimated that miRNAs regulate 30 to 60% of protein-coding genes.

• MiRNAs are involved in the regulation of genes related to many biological processes, such as cell proliferation and apoptosis.

• However, their main function is to establish and maintain the differentiated status of many cell types.

• They are located in different regions of the genome; 70% are intragenic, and the host gene and miRNAs invariably have the same orientation and are expressed together because both are controlled by the same promoter region.

• Several other miRNAs with altered expression in cancers have been identified, and many causes for their deregulation have been discovered.

• A systematic analysis of the locations of miRNAs in the mammalian genome has shown that more than 50% of them are located in fragile genomic sites, regions of loss of heterozygosity (LOH), minimal amplicons, and regions more susceptible to mutations, breaks and rearrangements, all situations frequently found in tumor cells .

• Thus, changes in the copy number of miRNA genes have an important role in tumor formation.

Nomenclature• Under a standard nomenclature system, names are assigned

to experimentally confirmed miRNAs before publication of their discovery.

• prefix "miR" is followed by a dash and a number , the latter often indicating order of naming.

• "miR-" refers to the mature form of the miRNA. "mir-" refers to the pre-miRNA and the pri-miRNA. "MIR" refers to the gene that encodes them.

Biogenesis

Source :- The Role of MicroRNAs in Cholesterol Efflux and Hepatic Lipid Metabolism by Kathryn J. Moore, Katey J. Rayner, Yajaira Su´arez, and Carlos Fern´andez-Hernando (Annual Review of Nutrition Vol. 31: 49-63 (Volume publication date August 2011,First published online as a Review in Advance on May 3, 2011)

Functions of miRNAs

Tumor suppression and oncogenes-

• About 50% of the annotated human miRNAs map within fragile sites of chromosomes, which are areas of the genome that are associated with various human cancers.

• Recent evidence indicates that miRNAs can function as tumour suppressors and oncogenes, and they are therefore referred to as ‘oncomirs’.

• Gene therapies that use miRNAs might be an effective approach to blocking tumour progression. miRNAs such as let-7, which has been shown to negatively regulate the Ras oncogenes, and miR-15 and miR-16, which negatively regulate BCL2, are promising candidates for cancer treatment.

MiRNAs and cancer development

• The first cancer-associated miRNAs were miR-15a and miR-16-1, which are located in the human chromosome 13q14 region, between exons 5 and 6 of the LEU2gene, a region frequently deleted in chronic lymphocytic leukemia (CLL) that progresses to an aggressive state

Source :- Oncomirs — microRNAs with a role in cancer by Aurora Esquela-Kerscher and Frank J. Slack, Published in final edited form as: Cancer J. 2012 May; 18(3): 223–231.

Role of mi RNA as biomarker in cancer diagnosis

microRNA: a new class of biomarkersSmall noncoding RNAs that regulate gene expression by binding complementary sequences of target mRNAs and inducing their degradation or translational repression

Evolutionary conserved

One miRNA has multiple targets

miRNAs: as biomarkers for diagnosis of breast cancer• Breast cancer affects approximately 12% women worldwide

and results in 14 % of all cancer-related fatalities.

• The most severe form of breast cancer is metastasis, when the tumor spreads from the breast tissue to other parts of the body.

• Importantly, miRNAs are found circulating in the blood, presenting an opportunity to use these circulating disease-related miRNAs as biomarkers.

• Clearly, the identification of circulating miRNAs specific to metastatic breast cancer presents a unique opportunity for early disease identification and for monitoring disease burden.

For Cigarette Smokers:

• MiRNA downregulation is a reversible event in cases of short-term exposure to cigarette smoke but becomes irreversible after long-term exposure, thus committing a cell to cancer development.

• For cigarette smoke-induced lung cancer, both DNA damage and miRNA alteration have to occur for full-blown cancer to develop.

• Cigarette smoke induces early DNA damage by promoting DNA adduct formation and mutations in oncogenes, such as K-ras .

• However, the expression of mutated oncogenes is silenced by the physiological expression of specific miRNAs, such as those belonging to the let-7 family, which targets K-ras gene products.

• When let-7 becomes irreversibly downregulated due to long-term cigarette smoke exposure, cells exhibit uncontrolled expression of mutated K-ras and become committed to cancer development.

miRNAs: as therapeutics• The first microRNA based therapy specifically for cancer is

MRX34: a synthetic miR-34a mimic loaded in liposomal nanoparticles .

• miR-34a is a tumor suppressor microRNA downstream of p53.

• Its replacement in cancer cells antagonizes key hallmarks including self-renewal, migratory potential, and chemo-resistance

• The most advanced microRNA trial involves use of anti-miR-122 (Miravirsen) for hepatitis C therapy , which shows reduction in viral RNA with no evidence of resistance.

• Miravirsen is complementary in sequence to miR-122 but also has a modified locked-nucleic acid structure, which provides resistance to degradation and increased affinity for its target.

• More recent studies have shown that although the intended target of Miravirsen is mature miR-122, it also has affinity for pri- and pre-miR-122 leading to reduced processing and enhancement of its therapeutic effect

Regulation of miRNAs

The need :-• Many miRNAs are expressed in a tissue-specific or developmental

stage- specific manner, thereby greatly contributing to cell-type-specific profiles of protein expression.

• With the potential to target dozens or even hundreds of different mRNAs, individual miRNAs can coordinate or fine-tune the expression of proteins in a cell.

• These considerations call for a tight and dynamic regulation of miRNA levels and activity, particularly during rapid developmental transitions or changes in cellular environment.

Regulation of miRNAs

Regulation of transcription

Stimulates expression of miR-34 and miR-107 which enhances cell cycle arrest and apoptosis

Stimulates expression of oncogenic miRNAs but inhibits expression of tumor suppressor miRNAs

Source :- The widespread regulation of microRNA biogenesis, function and decay by Jacek Krol, Inga Loedige and Witold Filipowicz. Published online 27 July 2010

Future perspectives• The past several years have witnessed tremendous

progress in our understanding of miRNAs.

• Still several important questions remain to be answered.

• Understanding how miRNAs are processed and how they are integrated into the complex regulatory networks will be crucial.

• Considering the fundamental role of miRNAs in organismal development, cellular differentiation and metabolism, viral infection, and oncogenesis, we can anticipate many more sophisticated mechanisms for the regulation of their biogenesis, function and catabolism to emerge in coming years.

References• The widespread regulation of microRNA biogenesis, function and

decay by Jacek Krol, Inga Loedige and Witold Filipowicz.

• MicroRNA Functions by Natascha Bushati and Stephen M. Cohen.

• MicroRNA-9a ensures the precise specification of sensory organ precursors in Drosophila by Yan Li, Fay Wang, Jin-A Lee, et al.

• Oncomirs — microRNAs with a role in cancer by Aurora Esquela-Kerscher and Frank J. Slack