Role of dietary ethiological factors in the molecular pathogenesis of liver cancer
Author
Gürsoy Yüzügüllü, Şehriban Özge
Advisor
Öztürk, Mehmet
Date
2011Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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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.