The role of Nrf2 in colorectal tumor malignancy
博士 === 中山醫學大學 === 醫學研究所 === 104 === Differences in subcellular localization of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have been associated with poor outcomes in human cancers. However, the prognostic value of subcellular localization of Nrf2 in colorectal cancer and the underlying mechan...
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ndltd-TW-104CSMU55340042017-10-01T04:30:24Z http://ndltd.ncl.edu.tw/handle/19100252397142539649 The role of Nrf2 in colorectal tumor malignancy Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) 參與結直腸癌腫瘤惡化之角色 Po-Lin Lin 林伯霖 博士 中山醫學大學 醫學研究所 104 Differences in subcellular localization of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have been associated with poor outcomes in human cancers. However, the prognostic value of subcellular localization of Nrf2 in colorectal cancer and the underlying mechanism in tumor invasion remain unknown. We enrolled tumors from colorectal patients to evaluate Nrf2, NQO1, and HO-1 expression by immunohistochemistry. NQO1 and HO-1 positive tumors showed nearly complete expression of Nrf2 in the nucleus and/or showed partial expression in the nucleus/cytoplasm (nNrf2); however, tumors negative for NAD(P)H-quinone oxidoreductase 1 (NQO1) and Heme oxygenase-1 (HO-1) showed almost complete expression of Nrf2 in the cytoplasm and/or partial expression in the nucleus/cytoplasm (cNrf2). Kaplan-Meier and Cox regression analysis indicated poorer overall survival in patients with cNrf2 tumors than with nNrf2 tumors. Cell models provided evidence that cNrf2, rather than nNrf2, was responsible for cell invasion and soft agar growth triggered by activation of the NF-κB/AKT/β-catenin cascade. Mechanistically, cNrf2 persistently increased PSMD4 expression by the HIF1α/β-catenin axis, whereas PSMD4 reciprocally enhanced Nrf2 nuclear export by increasing CRM1 expression through p53 degradation. The mechanistic action of the cell model was further confirmed with a nude mouse animal model in which xenograft tumors induced by cNrf2 were nearly completely suppressed by the proteasomal inhibitor carfilzomib or the β-catenin inhibitor XAV939. We therefore suggest that PSMD4 or β-catenin might be potential targets for suppressing tumor aggressiveness, and consequently, improving outcomes in patients whose tumors express cNrf2. Jinghua Tsai Chang Huei Lee 蔡菁華 李輝 2016 學位論文 ; thesis 90 en_US |
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博士 === 中山醫學大學 === 醫學研究所 === 104 === Differences in subcellular localization of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have been associated with poor outcomes in human cancers. However, the prognostic value of subcellular localization of Nrf2 in colorectal cancer and the underlying mechanism in tumor invasion remain unknown. We enrolled tumors from colorectal patients to evaluate Nrf2, NQO1, and HO-1 expression by immunohistochemistry. NQO1 and HO-1 positive tumors showed nearly complete expression of Nrf2 in the nucleus and/or showed partial expression in the nucleus/cytoplasm (nNrf2); however, tumors negative for NAD(P)H-quinone oxidoreductase 1 (NQO1) and Heme oxygenase-1 (HO-1) showed almost complete expression of Nrf2 in the cytoplasm and/or partial expression in the nucleus/cytoplasm (cNrf2). Kaplan-Meier and Cox regression analysis indicated poorer overall survival in patients with cNrf2 tumors than with nNrf2 tumors. Cell models provided evidence that cNrf2, rather than nNrf2, was responsible for cell invasion and soft agar growth triggered by activation of the NF-κB/AKT/β-catenin cascade. Mechanistically, cNrf2 persistently increased PSMD4 expression by the HIF1α/β-catenin axis, whereas PSMD4 reciprocally enhanced Nrf2 nuclear export by increasing CRM1 expression through p53 degradation. The mechanistic action of the cell model was further confirmed with a nude mouse animal model in which xenograft tumors induced by cNrf2 were nearly completely suppressed by the proteasomal inhibitor carfilzomib or the β-catenin inhibitor XAV939. We therefore suggest that PSMD4 or β-catenin might be potential targets for suppressing tumor aggressiveness, and consequently, improving outcomes in patients whose tumors express cNrf2.
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author2 |
Jinghua Tsai Chang |
author_facet |
Jinghua Tsai Chang Po-Lin Lin 林伯霖 |
author |
Po-Lin Lin 林伯霖 |
spellingShingle |
Po-Lin Lin 林伯霖 The role of Nrf2 in colorectal tumor malignancy |
author_sort |
Po-Lin Lin |
title |
The role of Nrf2 in colorectal tumor malignancy |
title_short |
The role of Nrf2 in colorectal tumor malignancy |
title_full |
The role of Nrf2 in colorectal tumor malignancy |
title_fullStr |
The role of Nrf2 in colorectal tumor malignancy |
title_full_unstemmed |
The role of Nrf2 in colorectal tumor malignancy |
title_sort |
role of nrf2 in colorectal tumor malignancy |
publishDate |
2016 |
url |
http://ndltd.ncl.edu.tw/handle/19100252397142539649 |
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