Abstract
Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7−/−) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-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 Nudt7−/− and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7−/− colons. Upregulated levels of β-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7−/− mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7−/− mice. We observed an increased level of palmitic acid in the colon of Nudt7−/− mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.
Highlights
Colorectal cancer (CRC) is one of the most common cancers, with over one million new cases diagnosed worldwide each year
To assess the alteration of lipid metabolism in KrasG12D colorectal cancer (CRC) compared with Kras wild-type (KrasWT) CRC, we analyzed lipid reactive oxygen species (ROS) and lipid accumulation in KrasG12D CRC cells (SNU-407, SNU-C2A, and LS-174T) and KrasWT cells (COLO-320DM, HT29, and Caco2)
To assess the alteration of lipid metabolism in KrasG12D CRC compared with KrasWT CRC, we WT(SNU-407, analyzed lipid reactive species (ROS)increased and lipid accumulation in KrasG12D of cells and lipid ROS-positive cellsoxygen was significantly
Summary
Colorectal cancer (CRC) is one of the most common cancers, with over one million new cases diagnosed worldwide each year. It is the third most common malignancy and the second most common cause of cancer mortality [1]. Fatty acid β-oxidation, is an essential process for cancer cell proliferation, differentiation, motility, and growth [9,10]. A study demonstrated that the Kras-dependent regulation of lipid metabolism is a critical factor for lung tumorigenesis [15] and fatty acid-induced inflammatory mediators such as prostaglandin E2, leukotriene B4, interleukin 1β, and tumor necrosis factor α, are known to act as stimulatory factors for cancer cell growth and proliferation [16].
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