Investigating the molecular mechanisms of natural dietary compounds in inhibiting colorectal carcinogenesis and malignant colorectal tumor growth

Abstract

Colorectal cancer (CRC) is one of the major causes of cancer-related mortality in both men and women worldwide Epidemiological studies demonstrated that environmental and lifestyle factors have been strongly associated with CRC development Environmental and industrial pollutant are difficult to avoid given their ubiquity in our global society During the recent decade food contamination (partially derived from environmental contaminants) has become increasingly serious matters as these factors elevate the risk of chemical contaminant-induced CRC Natural dietary compounds also called phytochemicals chemopreventive agents exhibited several beneficial effects for the prevention of disease and the inhibition of chemically-induced carcinogenesis Of note the majority of cancer chemopreventive agents inhibit cancer growth by activating programmed cell death (PCD) mechanisms such as apoptosis and autophagy Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are pervasive in the environment and are a potential source of food contamination with their ingestion via dietary sources greatly increasing CRC risk The aim of the first part of this study is to evaluate the mechanism and efficacy of polymethoxyflavones (PMFs) supplementation on the colorectal development in 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 PMF-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 inhibited inflammation activated anti-oxidation targets suppressed metastasis genes and ameliorate autophagic defect Additionally consumption of PMFs 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 These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis In the second part we investigated the underlying molecular mechanisms of Se-allylselenocysteine (ASC)-induced PCD and protocadherin 17 (PCDH17) expression in human colorectal adenocarcinoma HT-29 cell lines The autophagic cell death is the cause in ASC-induced cytotoxicity that was inhibited by pretreatment with autophagy inhibitor At the molecular level ASC induced PCDH17 expression through decreased PCDH17 promoter hypermethylation PCDH17 is also an important role in ASC-induced autophagy by HT-29 transfected with PCDH17 shRNA or expression plasmid Our western blot analysis showed that ASC significantly induced autophagy via the AMPK/mTOR pathway that was also regulated PCDH17 expression Additionally we used the HT-29 tumor xenograft models to confirm the ability of ASC inhibited tumor growth These results reveal that ASC is an effective inducer of autophagy through regulating the AMPK/mTOR and PCDH17 expression via epigenetic modification

Date of Award	2020
Original language	English
Supervisor	Ying-Jan Wang (Supervisor)