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" Understanding the Potential of microRNAs as Novel Therapeutic Targets in Cancer "
Lim, Lionel
Goga, Andrei
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Latin Dissertation
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English
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898250
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TL8zk4v5sq
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| Main Entry
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Lin, Pin Hsin
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Understanding the Potential of microRNAs as Novel Therapeutic Targets in Cancer\ Lim, LionelGoga, Andrei
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2013
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2013
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| Abstract
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Cancer is a complex and heterogenous disease triggered by a myriad of genetic and lifestyle factors. Decades of research have furthered our understanding of key oncogenes, tumor suppressor genes and signaling pathways, leading to the development of numerous effective cancer therapies. However, the dysregulation of multiple signaling pathways through aberrant gene expression makes existing treatment ineffective in many cancers, including hepatocellular carcinoma (HCC) and triple negative breast cancers (TNBCs). There is thus an urgent need to explore and develop novel therapeutics for the treatment of these widespread and fatal cancers. It is well established that microRNAs (miRNAs) are key players in both HCC and TNBC development, and exhibit aberrant processing and expression profiles in these cancers. Because a single miRNA could potentially affect several clinically relevant targets, artificially altering the expression level of a miRNA may effectively shut down multiple oncogenic pathways, offering effective therapeutic perspectives. In this thesis, we explored the potential of targeting an oncogenic miRNA in HCC. We find that miR-494 is upregulated in multiple mouse models and aggressive human HCC. We demonstrate that it accelerates G1/S cell cycle transition through regulation of Mutated in Colorectal Cancer (MCC) gene expression and show that its inhibition reduces transformation in human liver tumor cell lines and inhibits tumor growth in vivo. Separately, we explored the possibility of exploiting endogenous miRNA function to predict p53 expression, and consequently, therapeutic response in breast cancer. We find two SNPs in the p53 3' UTR, 485G>A and 826G>A, that are associated with mutant p53, and occur at higher frequencies in breast cancer patients than a diverse population. Further, we find that these SNPs lower p53 expression, possibly through creation of novel miRNA binding sites. Our findings indicate that miR-494 may have clinical value as a therapeutic target in HCC, and miRNA regulation of mutant p53 could be a predictor of therapeutic response in breast cancer.
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Lim, Lionel
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UCSF
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