Effect of RRM2 in Tumor Metastasis and Chemotherapy Response of Colorectal Cancer Patients with Different APC and K-Ras Status

Colorectal cancer (CRC) ranks as the third cause of cancer death in Taiwan. Even though numerous genes have been reported to be associated with tumorigenesis of colorectal cancer, only a few of them have been validated and used as biomarkers for early diagnosis, predicting metastasis, and treatment response in clinical applications. Overseas studies have found that the APC, K-ras, and p53 genes are mutated in a sizeable fraction of colorectal cancer (CRC). But, based on our preliminary results using tumor tissues of CRC patients, only 35% and 22.8% of CRC patients in Taiwan showed APC and k-ras gene mutation that was significantly lower than the other countries but the expression pattern was similar with the other countries. The mutation rate of p53 was similar with the other reports. These results suggested that there were different mechanism and clinical treatment of colorectal carcinogenesis existed in Taiwan and western countries. Previous reports found that high expression of RRM2 had a negative impact on the overall survival (OS) and progress-free survival (PFS) of CRC patients. In addition, RRM2 overexpression was associated with tumor metastasis and drug resistance of several types of cancer. Our previous report indicated that loss of APC gene expression were correlated with poor OS of CRC patients. The interaction between RRM2 and APC need further study. In this proposal, we integrated 8 program in order to understand the role of RRM2 in tumor metastasis and drug resistance of CRC patients with different APC and K-ras gene mutation status. The underlying molecular mechanism will be performed in human tissues, cell and animal models to understand which signaling pathway is involved in up-regulation of RRM2, the mechanism of RRM2 associated drug resistance, how to increase chemotherapy response, and the effect of RRM2 inhibitor in CRC treatment. The results obtained from this project may be used to predict therapeutic response in resected CRC patients with different APC/k-ras status, offering a possible strategy to overcome the drug resistance and consequently to improve outcome in CRC patients.