Study the Role and Regulation of Dicer in Sorafenib Sensitivity of Liver Cancer

Hepatocellular carcinoma (HCC) is the most common liver cancer worldwide. In patients with HCC, the prediction of prognosis is complex compared with most solid tumors. Liver cancer therapies are mainly limited to radiotherapy, surgical resection of tumor or targeted cancer therapies. Sorafenib is a first-line systemic drug for advanced HCC, but has only partial survival benefits and acquired drug resistance in HCC patients by long-term therapy. Investigation of molecular mechanisms of sorafenib resistance in liver cancer is an urgent and important issue. Recent evidence reveal that dysregulated miRNA expression of tumor cells may interfere with drug response. The miRNA-producing enzymes Dicer, a cytoplasmic endoribonuclease Type III, is crucial for the maturation of miRNAs. Therefore, alteration of Dicer expression may contribute to tumor progression, including clinical aggressiveness, prognosis and patient survival in various cancers. The roles and regulatory mechanisms of Dicer in acquired sorafenib resistance of liver cancer are still unknown. Our goal is to clarify whether Dicer affects the sorafenib resistance and the regulatory mechanisms involves in the pathophysiology of liver cancer. The specific aims as following will help us to achieve the goal. SPECIFIC AIM 1: To define the impact of Dicer in sorafenib sensitivity of liver cancer cells. 1-1. To establish sorafenib-resistant liver cancer cell lines. 1-2. To investigate the effects of Dicer in HCC progression, we win detect the sorafenib sensitivity; the cancer stem cell properties (sphere formation, stem cell markers such as CD133 or CD44, SOX2 or OCT4); and xenograft tumor formation in Dicer-overexpressed and -knocMowned HCC cells. 1-3. To define the correlation between Dicer expression and sorafenib-sensitivity in liver cancer patients. SPECIFIC AIM 2: To investigate the regulatory mechanism of Dicer in sorafenib sensitivity of liver cancer cells. 2-1. To define the differential regulatory mechanism of Dicer in sorafenib resistant liver cancer cells whether through transcriptional, post-transcriptional, translational, post-translational regulations or others. 2-2. To identify the candidate molecules involve in regulation of Dicer. 2-3. To confirm the linkage between candidate molecules, Dicer and subsequent biological functions. SPECIFIC AIM 3: To evaluate the physiological significance of candidate molecules and Dicer in animal model and liver cancer patients with sorafenib resistance. 3-1. To investigate the physiological significance of candidate molecules and Dicer in animal model. 3-2. To examine the clinical significance and sorafenib response of candidate molecules and Dicer in liver cancer patients. Accomplishments of these specific aims will help us to understand better about functions and molecular mechanisms of Dicer in liver cancer progression and sorafenib resistance. Furthermore, the findings from this project may provide more information for precision medicine in developing anti-liver cancer pharmaceuticals.