MCAT Biological and Biochemical Foundations of Living Systems: Passage 8 — Flashcards

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Noncoding RNA molecules have the potential to play important roles both in the development and treatment of cancer. Of the many classes of noncoding RNA molecules, two types are dysregulated in hepatocellular carcinoma (HCC) and various other types of cancer: microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). MiRNAs are short (21 to 23 nucleotides) single-stranded RNAs that are processed from longer precursor miRNAs and that are found in most organisms. This RNA species usually binds to messenger RNAs (mRNAs) that have regions of near-perfect complementarity, which represses translation or, in some cases, leads to cleavage of the mRN","LncRNAs, on the other hand, are generally defined as RNA molecules that are longer than 200 nucleotides. They often resemble mRNA molecules because of features such as being capped and polyadenylated, and they are actually more abundant than protein-coding RNAs in the cell. Although lncRNAs were originally thought of as transcriptional noise or artifacts of cloning, recent studies suggest that they play a number of regulatory roles in gene expression and in localization of proteins and subcellular structures; lncRNAs are also small RNA precursors. In the case of both miRNAs and lncRNAs, changes in expression levels have been associated with HCC survival and response to treatment. For example, overexpression of an lncRNA called HOTTIP may be responsible for chemoresistance. Decreased expression of a miRNA called miR26 has been associated with shorter survival but also superior response to interferon therapy for hepatitis C virus (HCV), whereas decreased expression of miR122 has also been linked with poor progression in patients with HCC. The differential expression of noncoding RNA in HCCs suggests that these molecules could serve as biomarkers if the differential expression can be shown more consistently among studies than it has been to date. There is particular need for noninvasive biomarkers that allow detection of early HCC. Several properties of RNAs make them attractive clinical tools, including the fact that they can be detected in patient sera, they are stable, and sensitive detection methods are available, such as microarray and polymerase chain reaction. On the therapeutic side, noncoding RNAs have become new molecular targets for HCC drugs. The leading drug candidate is called Miravirsen, and it inhibits miR122, which is required for replication of HCV. Miravirsen is currently in phase II clinical trials. Another class of noncoding RNAs, called short interfering RNAs (siRNAs), is also being developed as a potential HCC therapeutic. Although siRNAs are not normally expressed in human cells, the potent ability of these 22-nucleotide molecules to bind and degrade mRNAs with complementary sequence makes them highly valuable tools for targeting cellular proteins. Similar to miRNAs, siRNAs can be processed from a double-stranded RNA molecule by a cellular protein called Dicer. One siRNA-based treatment for primary as well as metastatic liver cancer destroys the RNAs encoding kinesin spindle protein and vascular endothelial growth factor. Currently, this drug has been found to be safe in phase I clinical trials. Furthermore, siRNAs could be developed that target lncRNAs that are critical for the development of progression of HCC. As more clinical studies are conducted on these novel drug candidates, several obstacles will need to be overcome. Major challenges include the off-target effects of short noncoding RNAs: both miRNA and siRNA species have been reported to bind mRNAs with imperfect complementarity and cause their translational repression. In addition, the clinical application of noncoding RNAs will require improved chemical formulations that ensure their delivery to appropriate tissues in the body.