Biomarkers for the Early Prediction and Prognosis for Colorectal Cancer---Construction of Kinetic

Colorectal cancer (CRC) is the second most common cancer and is also the third leading cause of cancer death in Taiwan. Surgery remains the mainstay of therapy, but recurrence after surgery of CRC occurs at a constant rate according to the stage of the disease. Although chemotherapy has also been applied in the treatment of colorectal cancer, a large amount of poorer responses still exist. Therefore it is valuable to discover the significant predictive biomarkers and to develop novel inhibitors to specifically block the pathogenesis of colorectal cancer. Our preliminary data indicated the dysfunction of store-operated calcium signaling in the colorectal cancer cells. It is known that calcium sensor STIM1 can physically interact with another protein called Orai1 to control the store-operated calcium influx. However, the molecular mechanism of how store-operated calcium channel involves in controlling the pathogenesis of colorectal cancer is still elusive. We plan to conduct a series of experiments to address this question. The specific aims to be tested are: (1) to identify novel mutations in store-operated calcium channel from colorectal cancer patients (2) to study the mechanisms of how Ca2+ microdomains regulate invadopodium formation, kinase cascades and tumor development. The proposal is innovative because 1) our study will allow us to understand the molecular mechanisms of how somatic mutations in calcium channel involves in tumorgenesis which may facilitate us to find potential targets for drug development; 2) we study a novel functions of calcium microdomain, which has little knowledge in controlling cancer; 3) we will employ NGS platform to screen store-operated calcium pathways in Taiwanese colorectal cancer patients which may increase the opportunity to find out new biomarkers; 4). Using a combination of molecular biological tools (genotyping, exon sequencing and gene stably expressing cells) and physiological approaches (Ca2+ imagine, high-resolution microscope), our study will be helpful in the treatment of colorectal cancer.