The goal of this research is to develop a novel molecular therapeutic strategy for treatment of hepatocellular carcinoma (HCC). HCC is currently one of the most frequent causes of cancer death worldwide. Oncogenic mutations in beta-catenin are commonly observed in HCC. These result in activation of the Wnt/beta-catenin pathway, a signaling mechanism that promotes cancer but also has an essential function in normal cells. Our preliminary data indicate that small interfering RNAs (siRNA) can specifically target the mutant beta-catenin transcripts found in cancer cells with minimal effects on wild-type sequences. Thus we hypothesize that Wnt signaling can be inhibited in HCC with minimal collateral damage to normal tissues. We will test this strategy using hepatoma cell lines with known beta-catenin mutations, and generate new cell lines from primary clinical material. Optimal siRNA sequences will be identified by testing their ability to modulate beta-catenin abundance and signaling. Hepatoma cells will then be produced that express mutation-specific beta-catenin siRNA in an inducible manner. These will be used to evaluate the phenotypic effects of diminished beta-catenin on cell growth parameters, differentiation, and apoptosis. We will also test the tumor-specific RNAi strategy in preclinical models of HCC in vivo so as to facilitate translation of this strategy towards future clinical application.
|Effective start/end date||31/7/17 → …|
- Qatar National Research Fund (QNRF)
- Oncogene; Wnt signalng; Liver cancer; RNAi;
- Experimental Therapeutics