Study the Effects and Regulation of Dicer in Gemcitabine Sensitivity of Pancreatic Cancer

Pancreatic cancer is a common malignancy with the poor prognosis in the world. Therefore, more understanding of the mechanisms involves in progression of pancreatic cancer may provide more potential therapeutic strategy. Gemcitabine has been a commonly used therapeutic agent for pancreatic cancer. However, resistance to gemcitabine has been seen in clinical trials in patients with pancreatic cancer. Recent evidences reveal that deregulated miRNA expression patterns 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. The expression of Dicer directly influences the biosynthesis of all microRNAs; therefore its altered expression may contribute to tumor progression. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis and patient survival in various cancer types. The molecular mechanisms of Dicer in acquired gemcitabine resistance of pancreatic cancer are still not clear. Our goal is to investigate whether Dicer affects the gemcitabine resistance and the molecular mechanisms involves in this pathophysiology of pancreatic cancer. The specific aims as following will help us to reveal the goal. SPECIFIC AIM 1: To define the impact of Dicer in gemcitabine sensitivity of pancreatic cancer cells. 1-1. To establish gemcitabine-resistant pancreatic cancer cell lines. 1-2 To define the role of Dicer in pancreatic cancer progression by database search. 1-3. To investigate the effects of Dicer in gemcitabine sensitivity of PDAC, we will detect the gemcitabine sensitivity in Dicer overexpressed and knockdowned PDAC cell. We will also detect the cancer stem cell properties (side population, sphere formation and stem cell markers, such as CD24, CD44, ESA or ALDH) to see whether Dicer’s impact results from regulation of CSC population. SPECIFIC AIM 2: To investigate the regulation of Dicer in gemcitabine resistance of PDAC. 2-1. To define the regulatory mechanism of Dicer whether through transcriptional, post-transcriptional, translational, post-translational regulation or others. 2-2. To identify the candidate molecules involves in regulation of Dicer. 2.3 To confirm the linkage between candidate molecules, Dicer and subsequent biological functions. 2-4 To further evaluate the synergistic effects of candidate molecules inhibitor in gemcitabine-resistant pancreatic cancer. SPECIFIC AIM 3: To evaluate the biological significance of candidate molecules and Dicer in animal model and pancreatic cancer patients with gemcitabine resistance. 3-1. To investigate the biological significance of candidate molecules and Dicer in animal model. 3-2. To examine the clinical significance of candidate molecules and Dicer in pancreatic cancer patients. Achievements of these specific aims will help us to understand better about functions and molecular mechanism of Dicer in pancreatic cancer progression. Furthermore, the findings from this project may provide more diagnostic and therapeutic targets in developing anti-pancreatic cancer pharmaceuticals.