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Jihye Kim's final dissertation.pdf (2.85 MB)

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microRNA regulation of CD44 and CD151 in hepatocellular carcinoma: Implications for novel therapies

Kim, Ji Hye
http://rave.ohiolink.edu/etdc/view?acc_num=osu1436954441

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, accounting for an estimated 745,000 deaths per year, representing 10% of all deaths from cancer. Most patients present with advanced HCC for which the overall survival is poor due to rapid tumor progression, metastasis and lack of effective treatments. Sorafenib is the first-line treatment for the advanced HCC, however sorafenib treatment showed clinically modest improvement and a number of patients develop resistance to sorafenib. There exists an urgent need to better understand the molecular mechanisms of the development of HCC and the resistance to current therapy and to develop new therapeutic options for advanced or recurrent HCC. We confirm previous findings that low miR-199a-3p expression is correlated with poor survival in HCC and that miR-199a-3p is significantly down-regulated in HCC. We identify a direct target of miR-199a-3p in HCC and reintroduction of miR-199a-3p to HCC cells strikingly suppressed cell migration and invasion in vitro in part by targeting CD151. In addition, a new bioanalytical method is validated to quantify miR-199a-3p levels in plasma and liver tissue for future Pharmacokinetic/Pharmacodynamic in vivo study. This bioanalytical method can be applied to other oligonucleotides therapeutic agents. miR-221 expression is upregulated in HCC patients. CD44 is responsible for cell-cell interaction, cell adhesion, cell migration and invasion and an important cancer stem cell marker. We report a direct correlation between miR-221 and CD44 expression in HCC cells; miR-221 and CD44 are low in epithelial-like HCC cells and high in mesenchymal-like HCC cells. Inhibition of miR-221 with antisense oligonucleotide negatively regulates CD44 expression at the translational level through the P13K-AKT-mTOR signaling pathway. The PI3K/AKT/mTOR signaling pathway is abnormally activated in HCC and sorafenib resistant cells. However, a recent phase III clinical trial with the allosteric mTOR inhibitor, everolimus failed to show better overall survival in patients with advanced HCC who were resistant or intolerant to sorafenib. Here we report that the ATP-competitive mTOR inhibitors showed better anti-proliferative and anti-migration effects on the mesenchymal-like HCC cells and sorafenib resistant HCC cells compared to everolimus. ATP-competitive mTOR inhibitors suppress CD44 expression by blocking phosphorylation of eukaryotic translation initiation factor eIF4E-binding protein 1, suggesting that ATP-competitive mTOR inhibitors would be more effective in treating the advanced HCC patients who are insensitive or resistant to sorafenib. Since miRNAs target entire pathways, miRNA-based therapy could be an effective option for treating HCC patients. miRNA-based therapy can be combined with small molecule ATP-competitive mTOR inhibitors such as INK128. We show here that these agents produce anti-proliferative and anti-migratory effects on mesenchymal-like HCC cells as well as sorafenib resistant HCC cells. Taken together, our findings aid in our understanding of the molecular mechanisms of sorafenib resistance in HCC and could contribute to the development of alternative strategies for treating advanced HCC who are intolerant or resistant to the current therapy.
Thomas Schmittgen (Advisor)
138 p.
Pharmaceuticals

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Citations

  • Kim, J. H. (2015). microRNA regulation of CD44 and CD151 in hepatocellular carcinoma: Implications for novel therapies [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436954441

    APA Style (7th edition)

  • Kim, Ji Hye. microRNA regulation of CD44 and CD151 in hepatocellular carcinoma: Implications for novel therapies. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1436954441.

    MLA Style (8th edition)

  • Kim, Ji Hye. "microRNA regulation of CD44 and CD151 in hepatocellular carcinoma: Implications for novel therapies." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436954441

    Chicago Manual of Style (17th edition)

osu1436954441
137
© 2015, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.