Role of dietary ethiological factors in the molecular pathogenesis of liver cancer

Abstract

Hepatocellular carcinoma is ranked third foremost cause of cancer deaths. Dietary factors play a crucial role in the molecular pathogenesis of liver cancer. Oxidative stress is usually coupled with the malignancy and progression of HCC since it is considered as a common factor during inflammation after chronic viral infection. Chemical stress caused by aflatoxin exposure, metabolic stress produced by alcohol abuse and selenium deficiency as a risk factor for HCC are associated with oxidative stress. It should be eliminated with an intact antioxidant defense mechanism. It is a major cause of genotoxicity endogenously through metabolic stress and exogenously produced by chemical and physical carcinogens. Even though the contribution of dietary factors in HCC progression has been established, the underlying molecular mechanism has not been fully understood. Cancer cells may respond to genotoxic stress with a cryptic development of survival advantage mechanisms. Therefore we wanted to investigate this idea with dietary factors involved in liver cancer. In this work, we studied the implication of Se-deficiency in tumorigenesis of hepatocytes and the mechanism underlying the selective selection of aflatoxins for p53-249 mutation in HCC. Aflatoxins are the most potent naturally occurring carcinogens and may play a causative role in 5-28% of hepatocellular carcinomas, worldwide. Aflatoxins are activated in liver cells and induce principally G- >T mutations, including a codon 249 (G->T) hotspot mutation of TP53 gene that is specifically associated with aflatoxin-related hepatocellular carcinoma. However, our comparative analysis showed that R249S does not provide survival advantage at heterozygous state. Thus, the selection could be at the mutation induction stage. The lack of p53 activation in Aflatoksin B1 exposed HCC cells led us to test DNA damage response after aflatoxin exposure. Unexpectedly, DNA damage checkpoint response to aflatoxins has not been studied thoroughly before. Although, DNA damage checkpoint response acts as an anti-tumor mechanism by protecting genome integrity against genotoxic agents, this highly critical aspect of aflatoxin carcinogenicity is poorly known. Our findings provide evidence for the contribution of ERK, p38MAPK and PI3K/Akt survival pathways under selenium supplementation in some HCC cell lines. Apart from the effect of selenium deficiency, our results enlighten the aflatoxin carcinogenicity in vitro. Our study pointed out for a negligent G1 and G2/M checkpoint response to aflatoxin B1-induced DNA damage. This defective response may account mostly for mutagenic and carcinogenic influences of aflatoxins. It may also associate with the frequent induction of TP53 hotspot mutation in aflatoxin-related human HCC.