NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development
Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that <i>Kras<sup>G12D</sup></i>-driven CRC tumors demonstrate dysfunctional peroxisomal b-oxidation and identified <...
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doaj-0d02f44aa24e4309aba410bbfbc07a422020-11-25T02:28:13ZengMDPI AGCancers2072-66942020-03-0112357610.3390/cancers12030576cancers12030576NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC DevelopmentJinsoo Song0Sujeong Park1Jinjoo Oh2Deokha Kim3Ji Hyun Ryu4Won Cheol Park5In-Jeoung Baek6Xi Cheng7Xin Lu8Eun-Jung Jin9Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 54538, KoreaDepartment of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 54538, KoreaDepartment of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 54538, KoreaDepartment of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 54538, KoreaDepartment of Carbon Convergence Engineering, College of Engineering, Wonkwang University, Iksan, Chunbuk 54538, KoreaDepartment of Surgery, Wonkwang University School of Medicine, Iksan, Chunbuk 54538, KoreaAsan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, 05505, KoreaDepartment of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 54538, KoreaStudies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that <i>Kras<sup>G12D</sup></i>-driven CRC tumors demonstrate dysfunctional peroxisomal b-oxidation and identified <i>Nudt7</i> (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In <i>Kras<sup>G12D</sup></i>-driven CRC tumors, the expression level of <i>Nudt7</i> was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into <i>Nudt7</i> knockout (<i>Nudt7<sup>−/−</sup></i>) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of <i>Nudt7</i>-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of <i>Nudt7<sup>−/−</sup></i> and <i>Nudt7<sup>+/+ </sup></i>mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in <i>Nudt7<sup>−/−</sup> </i>colons. Upregulated levels of β-catenin were observed in the colons of <i>Kras<sup>G12D</sup> </i>and AOM/DSS<i>-</i>treated <i>Nudt7<sup>−/−</sup> </i>mice and downstream targets of β-catenin such as<i> Myc</i>,<i> Ccdn1, </i>and<i> Nos2</i>, were also significantly increased in the colon of <i>Nudt7<sup>−/−</sup> </i>mice. We observed an increased level of palmitic acid in the colon of <i>Nudt7<sup>−/−</sup> </i>mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of b-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal <i>NUDT7</i> in <i>Kras<sup>G12D</sup></i>-driven CRC development.https://www.mdpi.com/2072-6694/12/3/576peroxisomecolorectal cancerperoxisomal coenzyme a diphosphatase nudt7 (nudt7)palmitic acidβ-catenin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jinsoo Song Sujeong Park Jinjoo Oh Deokha Kim Ji Hyun Ryu Won Cheol Park In-Jeoung Baek Xi Cheng Xin Lu Eun-Jung Jin |
spellingShingle |
Jinsoo Song Sujeong Park Jinjoo Oh Deokha Kim Ji Hyun Ryu Won Cheol Park In-Jeoung Baek Xi Cheng Xin Lu Eun-Jung Jin NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development Cancers peroxisome colorectal cancer peroxisomal coenzyme a diphosphatase nudt7 (nudt7) palmitic acid β-catenin |
author_facet |
Jinsoo Song Sujeong Park Jinjoo Oh Deokha Kim Ji Hyun Ryu Won Cheol Park In-Jeoung Baek Xi Cheng Xin Lu Eun-Jung Jin |
author_sort |
Jinsoo Song |
title |
NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development |
title_short |
NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development |
title_full |
NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development |
title_fullStr |
NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development |
title_full_unstemmed |
NUDT7 Loss Promotes <i>Kras<sup>G12D</sup> </i>CRC Development |
title_sort |
nudt7 loss promotes <i>kras<sup>g12d</sup> </i>crc development |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-03-01 |
description |
Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that <i>Kras<sup>G12D</sup></i>-driven CRC tumors demonstrate dysfunctional peroxisomal b-oxidation and identified <i>Nudt7</i> (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In <i>Kras<sup>G12D</sup></i>-driven CRC tumors, the expression level of <i>Nudt7</i> was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into <i>Nudt7</i> knockout (<i>Nudt7<sup>−/−</sup></i>) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of <i>Nudt7</i>-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of <i>Nudt7<sup>−/−</sup></i> and <i>Nudt7<sup>+/+ </sup></i>mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in <i>Nudt7<sup>−/−</sup> </i>colons. Upregulated levels of β-catenin were observed in the colons of <i>Kras<sup>G12D</sup> </i>and AOM/DSS<i>-</i>treated <i>Nudt7<sup>−/−</sup> </i>mice and downstream targets of β-catenin such as<i> Myc</i>,<i> Ccdn1, </i>and<i> Nos2</i>, were also significantly increased in the colon of <i>Nudt7<sup>−/−</sup> </i>mice. We observed an increased level of palmitic acid in the colon of <i>Nudt7<sup>−/−</sup> </i>mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of b-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal <i>NUDT7</i> in <i>Kras<sup>G12D</sup></i>-driven CRC development. |
topic |
peroxisome colorectal cancer peroxisomal coenzyme a diphosphatase nudt7 (nudt7) palmitic acid β-catenin |
url |
https://www.mdpi.com/2072-6694/12/3/576 |
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