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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 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
Beddowes, E.J., Faux, S.P., Chipman, J.K., 2003. Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress. Toxicology 187, 101-115.
Ding, W., Petibone, D.M., Latendresse, J.R., Pearce, M.G., Muskhelishvili, L., White, G.A., Chang, C.-., Mittelstaedt, R.A., Shaddock, J.G., McDaniel, L.P., Doerge, D.R., Morris, S.M., Bishop, M.E., Manjanatha, M.G., Aidoo, A., Heflich, R.H., 2012. In vivo genotoxicity of furan in F344 rats at cancer bioassay doses. Toxicol. Appl. Pharmacol. 261, 164-171.
Dizdaroglu, M., 2015. Oxidatively induced DNA damage and its repair in cancer. Mutat. Res. Rev. Mutat. Res. 763, 212-245.
Dizdaroglu, M., 2012. Oxidatively induced DNA damage: mechanisms, repair and disease. Cancer Lett. 327, 26-47.
Fujimoto, A., Furuta, M., Totoki, Y., Tsunoda, T., Kato, M., Shiraishi, Y., Tanaka, H., Taniguchi, H., Kawakami, Y., Ueno, M., Gotoh, K., Ariizumi, S., Wardell, C.P., Hayami, S., Nakamura, T., Aikata, H., Arihiro, K., Boroevich, K.A., Abe, T., Nakano, K., Maejima, K., Sasaki-Oku, A., Ohsawa, A., Shibuya, T., Nakamura, H., Hama, N., Hosoda, F., Arai, Y., Ohashi, S., Urushidate, T., Nagae, G., Yamamoto, S., Ueda, H., Tatsuno, K., Ojima, H., Hiraoka, N., Okusaka, T., Kubo, M., Marubashi, S., Yamada, T., Hirano, S., Yamamoto, M., Ohdan, H., Shimada, K., Ishikawa, O., Yamaue, H., Chayama, K., Miyano, S., Aburatani, H., Shibata, T., Nakagawa, H., 2016. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat. Genet. 48, 500-509.
Furfaro, A.L., Traverso, N., Domenicotti, C., Piras, S., Moretta, L., Marinari, U.M., Pronzato, M.A., Nitti, M., 2016. The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance. Oxid Med. Cell. Longev 2016, 1958174.
Hickling, K.C., Hitchcock, J.M., Oreffo, V., Mally, A., Hammond, T.G., Evans, J.G., Chipman, J.K., 2010. Evidence of oxidative stress and associated DNA damage, increased proliferative drive, and altered gene expression in rat liver produced by the cholangiocarcinogenic agent Furan. Toxicol. Pathol. 38, 230-243.
Jackson, A.F., Williams, A., Recio, L., Waters, M.D., Lambert, I.B., Yauk, C.L., 2014. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol. Appl. Pharmacol. 274, 63-77.
Jaramillo, M.C., Zhang, D.D., 2013. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 27, 2179-2191.
Kansanen, E., Kuosmanen, S.M., Leinonen, H., Levonen, A.L., 2013. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol. 1, 45-49.
Karin, M., Dhar, D., 2016. Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis 37, 541-546.
Linhart, K., Bartsch, H., Seitz, H.K., 2014. The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol. 3, 56-62.
Moser, G.J., Foley, J., Burnett, M., Goldsworthy, T.L., Maronpot, R., 2009. Furan-induced dose–response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Experimental and Toxicologic Pathology 61, 101-111.
Murakami, S., Motohashi, H., 2015. Roles of Nrf2 in cell proliferation and differentiation. Free Radic. Biol. Med. 88, 168-178.
Poungpairoj, P., Whongsiri, P., Suwannasin, S., Khlaiphuengsin, A., Tangkijvanich, P., Boonla, C., 2015. Increased Oxidative Stress and RUNX3 Hypermethylation in Patients with Hepatitis B Virus-Associated Hepatocellular Carcinoma (HCC) and Induction of RUNX3 Hypermethylation by Reactive Oxygen Species in HCC Cells. Asian Pac. J. Cancer. Prev. 16, 5343-5348.
Schulze, K., Imbeaud, S., Letouze, E., Alexandrov, L.B., Calderaro, J., Rebouissou, S., Couchy, G., Meiller, C., Shinde, J., Soysouvanh, F., Calatayud, A.L., Pinyol, R., Pelletier, L., Balabaud, C., Laurent, A., Blanc, J.F., Mazzaferro, V., Calvo, F., Villanueva, A., Nault, J.C., Bioulac-Sage, P., Stratton, M.R., Llovet, J.M., Zucman-Rossi, J., 2015. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505-511.
Takahashi, S., Hirose, M., Tamano, S., Ozaki, M., Orita, S., Ito, T., Takeuchi, M., Ochi, H., Fukada, S., Kasai, H., Shirai, T., 1998. Immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine in paraffin-embedded sections of rat liver after carbon tetrachloride treatment. Toxicol. Pathol. 26, 247-252.
Totoki, Y., Tatsuno, K., Covington, K.R., Ueda, H., Creighton, C.J., Kato, M., Tsuji, S., Donehower, L.A., Slagle, B.L., Nakamura, H., Yamamoto, S., Shinbrot, E., Hama, N., Lehmkuhl, M., Hosoda, F., Arai, Y., Walker, K., Dahdouli, M., Gotoh, K., Nagae, G., Gingras, M.C., Muzny, D.M., Ojima, H., Shimada, K., Midorikawa, Y., Goss, J.A., Cotton, R., Hayashi, A., Shibahara, J., Ishikawa, S., Guiteau, J., Tanaka, M., Urushidate, T., Ohashi, S., Okada, N., Doddapaneni, H., Wang, M., Zhu, Y., Dinh, H., Okusaka, T., Kokudo, N., Kosuge, T., Takayama, T., Fukayama, M., Gibbs, R.A., Wheeler, D.A., Aburatani, H., Shibata, T., 2014. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267-1273.
Wacker, M., Wanek, P., Eder, E., 2001. Detection of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal after gavage of trans-4-hydroxy-2-nonenal or induction of lipid peroxidation with carbon tetrachloride in F344 rats. Chem. Biol. Interact. 137, 269-283.
Wang, E., Chen, F., Hu, X., Yuan, Y., 2014. Protective effects of apigenin against furan-induced toxicity in mice. Food Funct. 5, 1804-1812.
Wang, Y., Millonig, G., Nair, J., Patsenker, E., Stickel, F., Mueller, S., Bartsch, H., Seitz, H.K., 2009. Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease. Hepatology 50, 453-461.
Winczura, A., Zdzalik, D., Tudek, B., 2012. Damage of DNA and proteins by major lipid peroxidation products in genome stability. Free Radic. Res. 46, 442-459.
Xiang, M., Namani, A., Wu, S., Wang, X., 2014. Nrf2: Bane or blessing in cancer? J. Cancer Res. Clin. Oncol. 140, 1251-1259.
Zhang, T.T., Zhao, G., Li, X., Xie, F.W., Liu, H.M., Xie, J.P., 2015. Genotoxic and oxidative stress effects of 2-amino-9H-pyrido[2,3-b]indole in human hepatoma G2 (HepG2) and human lung alveolar epithelial (A549) cells. Toxicol. Mech. Methods 25, 212-222.