結直腸癌腫瘤組織中 AhR 與代謝蛋白表現對於 BPDE-like DNA 鍵結物含量與 p53 蛋白高度表現之相關性研究

Abstract

Neoplasm is the leading death of Taiwanese since 1982 and colorectal cancer is the third cause of cancer death. Epidemiological studies indicated that cigarette smoking and the consumption of red meat may increase the risk of colorectal cancer. They might consume relatively higher amounts of genotoxic or carcinogenic polycyclic aromatic hydrocarbons (PAHs) which can up-regulate the metabolic genes including CYP1A1, GSTM1, NQO1, and DDH through AhR/Nrf2 signaling pathways. The BaP active metabolite BPDE may then attack DNA to form BPDE-N2dG DNA adduct and to cause tumor suppressor gene p53 mutation, p53 genetic mutation has been demonstrated to be correlated with p53 overexpression in colorectal cancer. In this study, we investigated (1) whether p53 overexpression was a poor prognostic factor in Taiwanese colorectal cancer patients to suggest that p53 overexpression may play an important role in colorectal tumor progression, (2) whether BPDE-like DNA adducts was associated with p53 overexpression, (3) whether the metabolic enzymes of CYP1A1, GSTM1, NQO1, and DDH were induced by PAHs to involve in the formation of BPDE-like DNA adducts, (4) whether the induction of these metabolic genes was mediated through AhR signaling pathway, and (5) whether AhR protein expression was associated with p53 overexpression in colorectal tumors. The above gene expressions and BPDE-like DNA adducts in 152 colorectal tumors were all examined by immunohistochemistry (IHC). Our data indicated that the four metabolic protein expressions were significantly correlated with AhR protein expression such finding suggest that AhR pathway was markedly induced by the inducer such as PAHs. In addition, BPDE-like DNA adduct levels were positively correlated with CYP1A1, NQO1, and DDH protein expressions, and the adduct levels were also positively correlated with p53 overexpression. More interestingly, AhR protein expression was significantly correlated with p53 overexpression and this observation seems to support previous report indicated that AhR may promote the phosphorylation of p53 to stabilize p53 protein expression in tumor cells. In summary, p53 overexpression in colorectal tumors might associate with the induction of AhR signaling pathway by PAHs derived from cigarette smokes and cooked meats and BPDE-like DNA adducts were also associated with p53 overexpression. Thus, our data may support the possibility that the consumption of cigarette smokes and cooked meats may increase the risk of colorectal cancer.