Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate‐induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/β-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.

Integration Analysis of Differential Expressed Genes Regulated by Differential Methylated Regions for Predicting Prognosis in Human Colon Cancer

“…Similarly, in cellular companion (CC) module, there were 4 terms relative to molecular binding. Some reports found that retinoid acid binding receptor inhibited cancer cell apoptosis by regulating miR-22/NUR77 axis (21,22). Interestingly, from the results of KEGG pathway enrichment analysis, we found that the genes mainly enriched in molecular metabolism, being consistent with BP of GO enrichment, and the drug, retinoid and porphyrin metabolism are proved involving in irregulated tumor cell metabolism, and resulted in chemotherapy resistant (23).…”

“…A lot of reports show that retinoic acid metabolic process associates with colonic tumorigenesis and metastasis, such as retinoic acid metabolizing enzymes CYP26B1, LRAT and CYP26A1 over expressed in colorectal cancer tissues and that LRAT and CYP26B1 signi cantly associated with the prognosis of the colorectal cancers (19). Xenobiotic metabolic process also involves in the carcinogenesis and development of cancer, because colonic epithelium is exposed to various compounds from diet, and the compounds can be metabolized to the procarcinogens, which are the risks of colonic cancer (20,21). Similarly, in cellular companion (CC) module, there were 4 terms relative to molecular binding.…”

Antiproliferative Effects of Short-chain Fatty Acids on Human Colorectal Cancer Cells via Gene Expression Inhibition

“…This is the first report on the comprehensive analysis of the mechanism of the antitumor action of butyric acid, isobutyric acid, and acetic acid in human colon cancer cells. The Wnt/β-catenin, PI3K/Akt/mTOR and Ras/MEK/ERK signalling systems are known as oncogenic pathways of colorectal cancer (17)(18)(19). The analysis revealed that the main mechanism of the antitumor activity of SCFAs was suppression of tumour growth and metabolic functions such as cell cycle, DNA replication, recombination and repair, and almost no suppression of cancer-related genes.…”

Integrated Bioinformatics Analysis to Identify Abnormal Methylated Differentially Expressed Genes for Predicting Prognosis of Human Colon Cancer

“…Some reports found that retinoid acid binding receptor inhibited cancer cell apoptosis by regulating the miR-22/ NUR77 axis. 25,26 From the results of KEGG pathway enrichment analysis, we found that the genes were mainly enriched in molecular metabolism, and drug, retinoid and For personal use only.…”