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Oxidative Stress leads to Liver Cancer
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
There are a variety of ways in which oxidative stress can lead indirectly to cancer. The main routes involve: (a) reactive oxygen species (ROS) that cause cytotoxicity, followed by regenerative proliferation leading to cancer; (b) ROS-induced DNA damage leading to mutations in cancer-driver genes and subsequently cancer; and (c) oncogenic effects of the up-regulation of NRF2. The focus of this iKER is on (b) and (c), as the details of (a) are mapped out elsewhere.
Evidence Collection Strategy
Evidence Supporting this KER
The types of genotoxic oxidative DNA damage that may occur following exposure to ROS have been extensively reviewed previously (Dizdaroglu 2012, Dizdaroglu 2015). Briefly, ROS can react with nitrogenous bases to produce various adducts that may be converted into a mutation following DNA replication. Further, ROS can damage the sugar phosphate backbone of DNA leading to abasic sites and strand breaks. If DNA damage leads to mutations that increases the expression of oncogenes or decreases the expression of tumour suppressor or DNA damage repair genes, they will transform normal cells into malignant cells. It is generally thought that liver cancer results from an accumulation of mutations in key cancer-driving genes such as TP53 and CTNNB1 (Fujimoto, et al. 2016, Shibata and Aburatani 2014a) (http://atlasgeneticsoncology.org/Tumors/HepatoCarcinID5039.html).
In addition to DNA damage, at the molecular level, chronic activation of the Nrf2 oxidative stress response has been linked to promoting malignant transformation in pre-cancerous cells. Persistent Nrf2 activation results in the long-term up-regulation of antioxidant genes (which protect cancer cells that are known to have elevated ROS) and phase II metabolism genes (which facilitate the rapid metabolism of chemotherapeutics) (Kansanen, et al. 2013) providing a favourable environment for growth of pre-cancerous cells. The connection between chronically activated Nrf2 and cancer has been extensively studied and reviewed, most recently by Furfaro et al. (2016) and Karin and Dhar (2016). Further, Nrf2 control over cellular proliferation and differentiation has also been studied; reviewed most recently by Murakami and Motohashi (2015).
Uncertainties and Inconsistencies
Not all agents that cause ROS in the liver cause liver cancer. Thus, there are additional modulating factors that must be considered when determining whether a ROS-producing chemical will cause liver cancer.
Overall, ROS-dependent DNA damage causing harmful mutations is known to occur. However, the specific mechanism and the quantitative relationships by which these mutations promote malignant transformation are incompletely understood.
Increase in NRF2 expression is associated with occurrence and recurrence of hepatocellular carcinoma; however, the mechanism is incompletely understood.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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