Colorectal cancer (CRC) accounts for more than 9% of all of cancer, therefore, it is considered as one of the major contributors to mortality worldwide. Lifestyle factors such as smoking, diet, alcohol, physical inactivity are known to contribute to the incidence of CRC. Cooking of meats at high temperatures cause a creation of browned surface, which leads to the formation of dietary carcinogens that have been reported to be associated with the occurrence of CRC. Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine(PhIP) are two prominent examples of dietary carcinogens produced by cooking meat containing food at high temperature. Exposure to these dietary pro-carcinogens (BaP/PhIP) can lead to the formation of DNA adducts, causing DNA damage and mutations, via cytochrome P450 (CYP) enzyme metabolism. Moreover, inflammation of the colonic microenvironment supports the development and progression of CRC. Upregulation of inflammatory mediators and cytochrome P450 enzymes have been reported in CRC tissue, and they appear to promote tumorigenicity. Interleukin 8 (IL8) is known for its pro-inflammatory effect, whereas interleukin 10 (IL10) is an immunoregulatory interleukin which appears to have dual function as pro and anti-inflammatory mediator within the tumor microenvironment. Generally, interleukins have function roles in tumor progression by activation of signaling pathways, gene regulation, and DNA alteration. Therefore, I hypothesize that the increased levels of inflammatory mediators in colorectal cells can modify the activity of CYP450 and thus local activation of dietary-carcinogens, thereby enhancing the initiation and the development of CRC carcinogenesis. The hypothesis in this current project was investigated by using a mechanistic approach with in vitro cell culture techniques using 2 dimensional and 3 dimensional models.
In this current study, IL8 and IL10 showed an effect on BaP and PhIP induced genotoxic effect. Both chemicals (BaP and PhIP) on their own caused an increase in IL8 and IL10 levels. The expression of CYP1A1, CYP1B1 and CYP2E1 increased after IL8 and IL10 treatments. Moreover, co-treatment of BaP or PhIP with IL8 or IL10 also increased CYP1A1, CYP1B1, and CYP2E1 expression, causing increased activation of pro-carcinogen chemicals. This caused a significant increase in DNA damage with by BaP and PhIP compared to singular treatments with these chemicals. I therefore hypothesized that miRNAs, AhR, and STAT3 function in these results. MiR-27b did not appear to regulate the significant increase of CYP1B1 caused by IL8 treatment. IL10 induction by BaP was observed to be regulated by AhR inhibition and miR-132, while STAT3 inhibition and miR-212 were reported to regulate the expression IL8. Moreover, AhR inhibition clearly caused a decrease in CYP1A1 and CYP1B1 expression, with a reduction in MN number caused by BaP treatment.
Overall, these data suggest that IL8 and IL10 can influence the activation and genotoxicity of pro-carcinogen chemicals. More understanding of these mechanisms and events could facilitate the development of better treatment and therapeutic strategies of CRC.