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Key Points

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  • Summary:

    • (miRNAs or miRs) are 18 to 25 noncoding RNAs that have the capacity to regulate mRNA through degradation or inhibition of translation. miRNAs represent only one member of a larger family of noncoding RNAs many of whose function has yet to be elucidated.

    • Given the potential redundancy between a miRNA sequence (“seed” sequence) and multiple target mRNA sequences, miRNA can simultaneously target tens to hundreds of genes. As a result, it is estimated that more than 30% of the human genome is targeted by miRNA.

    • miRNAs have been implicated in the regulation of fundamental cellular processes including differentiation, growth, survival, and angiogenesis.

    • While, patterns of miRNA expression are being used for both diagnostic and therapeutic purposes, several challenges remain in the translation or miRNA biology to targeted therapies.

  • MicroRNA as diagnostic and prognostic biomarkers:

    • The global deregulation of miRNAs across malignancies supports their role in tumor development. These patterns of expression are being leveraged for both diagnostic and prognostic purposes.

  • Therapeutic applications for microRNA:

    • Given their capacity to simultaneously regulate multiple genes and thus essential biologic functions, miRNAs are reasonable candidates as targeted therapies. However, both minimizing off-target effects as well as achieving target organ or disease specificity are important challenges to effective miRNA therapy.

  • Delivery systems:

    • The majority of miRNA-based approaches to therapy have been conducted in vitro and in animal models of disease are still far from reaching human application. However, in one case, systemic delivery of miRNA-based agents has now reached clinical trial. Currently, a pharmaceutical-led clinical trial targeting the liver-specific miR-122 (SPC3649) is being tested as a therapy for Hepatitis C.

  • miRNAs and chemotherapeutics:

    • miRNAs may also have a role as either predictors or modifiers of response to traditional therapeutic agents.

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Molecular Genetics and Molecular Mechanism

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miRNAs or miRs are 18 to 25 noncoding RNAs that have the capacity to regulate mRNA through degradation or inhibition of translation. miRNAs represent only one member of a larger family of noncoding RNAs many of whose function has yet to be elucidated. The critical role for miRNAs in the development and progression of both solid and hematologic malignancies is increasingly apparent based on patterns of global deregulation, see Table 177-1. In addition, by targeting critical hallmarks to tumor development and progression, miRNAs may function as either tumor suppressors or oncogenes. miRNA biology is also being applied to nonmalignant disease involving the cardiac, endocrine, neurologic, and respiratory systems to name a few. There are several mechanisms for miRNA deregulation including chromosomal deletions, amplifications, and translocations, epigenetic modification, impaired processing, miRNA polymorphisms, and environmental factors. Some of the first expression studies in miRNA were conducted in hematologic malignancies. Investigators first observed that miR-15a and16-1 were located in a chromosomal region that was either deleted or downregulated in 68% of patients with chronic lymphocytic leukemia (CLL). This pattern of expression was associated with a more indolent form of disease. Since that initial observation, ...

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