| Summary: | 碩士 === 中山醫學大學 === 醫學分子毒理學研究所 === 99 === Nuclear factor E-2 related factor 2 (Nrf2)-Keap1 pathway has been shown to regulate antioxidant and Phase II gene expressions to protect cells against oxidative stress-induced apoptosis. Reactive oxygen species-mediated inflammation has been shown to link with colorectal carcinogenesis. For example, nitric oxide (NO)-induced Nrf2-keap activation may protect the oxidative DNA damage and apoptosis in colon carcinoma cells. Recently, Nrf2-knockdown suppresses tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and VEGF expression via inhibiting HIF-1α activation. Therefore, in the present study, we expect that Nrf2 expression may be associated with the clinical outcome in colorectal cancer patients. Immunohistochemistry analysis was performed to evaluate Nrf2 expression in tumor paraffin sections from 150 colorectal cancer patients. Our data showed that Nrf2 expression was not associated with clinico-pathological parameters in colorectal patients including age, gender, smoking status, stage, T, N, and disease relapse. Interestingly, Nrf2 expression was not only observed in tumor cell nucleus but also in cytoplasm; however, the association among cytoplasmic Nrf2 (C+/N-), cytoplasm plus nucleus (C+/N+), and Nrf2-negative (C-/N-) with clinico-pathological parameters was also not observed. Kaplan-Meier analysis showed that patients with Nrf2- positive expression including C+/N- plus C+/N+ had shorter overall survival and relapse free survival than those with Nrf2-negative expression (C-/N-). Moreover, Nrf2 (C+/N-) patients had the worst OS and RFS followed by patients with Nrf2 (C+/N+) and Nrf2 (C-/N-). Cox regression analysis indicated that patients with Nrf2-positive (C+/N-, C+/N+) and Nrf2 (C+/N-) were still to have poorer OS and RFS compared to those with Nrf2 (C-/N-) expression. Mechanistic studies indicated that the migration capability was remarkably increased by Nrf2-overexpression and decreased by Nrf2-knockdown in colorectal cancer cells. However, cell colony formation was slightly elevated in Nrf2-overexpression and reduced in Nrf2-knockdown colorectal cancer cells. The results from cell model experiments seemed to support our patient’s observation to suggest that Nrf2 expression, especially in the cytoplasm of tumor cells may independently predict poorer outcome in colorectal cancer patients.
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