مجال التميز | تميز دراسي و بحثي |
البحوث المنشورة |
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البحث (1): | |
عنوان البحث: |
Tumour necrosis factor-α (TNF-α) enhances dietary carcinogen-induced DNA damage in colorectal cancer epithelial cells through activation of JNK signaling pathway |
رابط إلى البحث: |
https://www.sciencedirect.com/science/article/pii/S0300483X21001293 |
تاريخ النشر: |
04/05/2021 |
موجز عن البحث: |
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death. Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazol [4,5-b] pyridine (PhIP) present in cooked meat are pro-carcinogens and considered to be potential risk factors for CRC. Their carcinogenic and mutagenic effects require metabolic activation primarily by cytochrome P450 1 family enzymes (CYPs); the expression of these enzymes can be modulated by aryl hydrocarbon receptor (AhR) activation and the tumour microenvironment, involving mediators of inflammation. In this study, we hypothesized that tumour necrosis factor-α (TNF-α), a key mediator of inflammation, modulates BaP- and PhIP-induced DNA damage in colon cancer epithelial cells. Importantly, we observed that TNF-α alone (0.1–100 pg/ml) induced DNA damage (micronuclei formation) in HCT-116 cells and co-treatment of TNF-α with BaP or PhIP showed higher levels of DNA damage compared to the individual single treatments. TNF-α alone or in combination with BaP or PhIP did not affect the expression levels of CYP1A1 and CYP1B1 (target genes of AhR signaling pathways). The DNA damage induced by TNF-α was elevated in p53 null HTC-116 cells compared to wild type cells, suggesting that TNF-α-induced DNA damage is suppressed by functional p53. In contrast, p53 status failed to affect BaP and PhIP induced micronucleus frequency. Furthermore, JNK and NF-κB signaling pathway were activated by TNF-α treatment but only inhibition of JNK significantly reduced TNF-α-induced DNA damage. Collectively, these findings suggest that TNF-α induced DNA damage involves JNK signaling pathway rather than AhR and NF-κB pathways in colon cancer epithelial cells. |
المؤتمرات العلمية |
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المؤتمر (1): | |
عنوان المؤتمر: |
10th International Conference on Research in Science and Technology |
تاريخ الإنعقاد: |
19/12/2020 |
مكان الإنعقاد: |
Oxford, UK |
طبيعة المشاركة: |
Paper presentation |
عنوان المشاركة: |
Tumour Necrosis Factor-α (TNF-α) enhance dietary carcinogen-induced DNA damage in colorectal cancer epithelial cells |
ملخص المشاركة: |
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death. The majority of CRC is sporadic and attributable to environment-induced gene mutations. Benzo(a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) are cocked food dietary carcinogens found in red or processed meats, one of the risk factors contributing to the development of colon cancer. Their carcinogenic and mutagenic effects require metabolic activation by cytochrome P450 enzymes (CYPs) such as CYP1A1 and CYP1B1; the ultimate carcinogenic metabolites bind covalently to DNA to cause DNA damage and mutations. The expression levels of CYP450 enzymes can be modulated under inflammatory conditions. As inflammation is known to contribute to carcinogenesis, we investigated the influence of a major proinflammatory cytokine Tumour necrosis factor-α (TNF-α) on BaP- and PhIP- induced DNA damage in colon cancer epithelial cells (HCT116) using an in vitro micronucleus (MN) assay. We also investigated the involvement of P53 in the observed effects using p53 null epithelial cells p53 (-/-). MN formation was increased following treatment with PhIP and BaP. Co- treatment with (TNF-α) at physiological and pathological concentration enhanced DNA damage in CRC cells. P53 was found mediated the (TNF-α) genotoxic effects in CRC cells. Our results indicated that inflammatory conditions enhance the genotoxic effects of the dietary carcinogens BaP and PhIP. |
الرابط: |
أمينه غازي ذعار العتيبي
دكتوراه
الطب والخدمات الصحية
Imperial College London