The current research indicates that the intestinal microbiota plays an important role in the homeostasis of the colon and, in accordance, that dysbiosis may be associated with colorectal cancer (CRC). In fact, the microbial byproduct butyrate is observed to induce anti-cancer effects, which has been suggested to be mediated through an ability to regulate gene expression. Our study attempts to elucidate the molecular mechanisms behind these anti-cancer effects of butyrate by conducting luciferase promoter-reporter assays of the genes APC, CDX2, SPINT1, CGN, TCF7L2, CK1, HBP1, YAP1, ST14, and SOX9, all important in intestinal homeostasis and the development of CRC. These results are combined with a bioinformatic analysis that aims to reveal transcription factors that could mediate this gene regulatory effect of butyrate. The bioinformatic analysis of potential transcription factor binding sites on the promoter regions of the genes of interest is investigated via the JASPAR database. Butyrate is found to upregulate the activity of the promoters of APC, CDX2, SPINT1, CGN, and TCF7L2, but not CK1 and HBP1. The results of YAP1, ST14, and SOX9 were inconclusive. From other studies investigating the functions of the gene products of the five upregulated genes, molecular mechanisms that could explain some of the observed anti-cancer effects of butyrate was deduced. Based on all the findings, a model for the mechanisms behind the anti-cancer effects of butyrate is proposed. These functions include repression of proliferation, both Wnt- dependent and -independent, repress oncogenic pathways, reduction of inflammation through maintenance of tight junctions, which are all associated with reduced risk of CRC. From the bioinformatic analysis, the transcription factors NF-kB and AP-1 seem like plausible candidates to mediate the gene regulatory effects of butyrate. Due to uncertainties in our experimental results and ambiguous functions of the gene products as well as of the transcription factor candidates, further investigations should be made to verify or falsify our proposed model of the mechanisms of butyrate.
|Uddannelser||Basis - Naturvidenskabelig Bacheloruddannelse, (Bachelor uddannelse) Bachelor|
|Udgivelsesdato||27 maj 2019|
- colon cancer
- colorectal cancer
- Intestinal homeostasis