Karaciğer kanserinin moleküler patogenezinde diyet etiyolojik faktörlerin rolü

Hepatocellular carcinoma is ranked third foremost cause of cancer deaths. Dietary factorsplay a crucial role in the molecular pathogenesis of liver cancer. Oxidative stress isusually coupled with the malignancy and progression of HCC since it is considered as acommon factor during inflammation after chronic viral infection. Chemical stress causedby aflatoxin exposure, metabolic stress produced by alcohol abuse and seleniumdeficiency as a risk factor for HCC are associated with oxidative stress. It should beeliminated with an intact antioxidant defense mechanism. It is a major cause ofgenotoxicity endogenously through metabolic stress and exogenously produced bychemical and physical carcinogens. Even though the contribution of dietary factors inHCC progression has been established, the underlying molecular mechanism has not beenfully understood.Cancer cells may respond to genotoxic stress with a cryptic development of survivaladvantage mechanisms. Therefore we wanted to investigate this idea with dietary factorsinvolved in liver cancer. In this work, we studied the implication of Se-deficiency intumorigenesis of hepatocytes and the mechanism underlying the selective selection ofaflatoxins for p53-249 mutation in HCC. Aflatoxins are the most potent naturallyoccurring carcinogens and may play a causative role in 5-28% of hepatocellularcarcinomas, 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 isspecifically associated with aflatoxin-related hepatocellular carcinoma.However, our comparative analysis showed that R249S does not provide survivaladvantage at heterozygous state. Thus, the selection could be at the mutation inductionstage. The lack of p53 activation in Aflatoksin B1 exposed HCC cells led us to test DNAdamage response after aflatoxin exposure. Unexpectedly, DNA damage checkpointresponse to aflatoxins has not been studied thoroughly before. Although, DNA damagecheckpoint response acts as an anti-tumor mechanism by protecting genome integrityagainst genotoxic agents, this highly critical aspect of aflatoxin carcinogenicity is poorlyknown.Our findings provide evidence for the contribution of ERK, p38MAPK and PI3K/Aktsurvival pathways under selenium supplementation in some HCC cell lines. Apart fromthe effect of selenium deficiency, our results enlighten the aflatoxin carcinogenicity invitro. Our study pointed out for a negligent G1 and G2/M checkpoint response toaflatoxin B1-induced DNA damage. This defective response may account mostly formutagenic and carcinogenic influences of aflatoxins. It may also associate with thefrequent induction of TP53 hotspot mutation in aflatoxin-related human HCC.