Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewReactive Oxygen Species (ROS)––Induced genetic and epigenetic alterations in human carcinogenesis
Introduction
The term “free radicals” refer to any molecular species with one or more unpaired electron(s), a characteristic that provides them with an “unstable” chemical nature and thus confers them with the property of being very reactive. It is indeed this property that when they react with DNA, RNA, proteins, and lipids, leads to cellular toxicity. Free radicals include both reactive oxygen (ROS; such as, superoxide (O2−), hydroxyl (OH−), hydroperoxyl (HOO−), peroxyl (ROO−) and alkoxyl (RO−) radicals [4], [7]) and nitrogen (RNS) species. In particular, ROS production can be of endogenous (mitochondrial and P450 metabolism, inflammatory cell activation, etc.) as well as of exogenous (radiation, ozone, etc.) origin. In fact, the majority of environmental, occupational and industrial pollutants are chemicals able to generate free radical species (primarily through their metabolic activation) that contribute to the pathophysiology of human disease including cancer. Finally, when ROS generation exceeds the cell's ability to metabolize and detoxify them, a state of “oxidative stress” emerges [45], [46], [47].
In general, cancer development is a multi-stage process characterized by the cumulative action of a number of altered cellular processes including those of replication, angiogenesis, apoptosis, metastasis etc. However, although some of these altered cellular processes have been extensively studied, there is still much to learn in regards to the molecular mechanism(s) involved. This is of great importance in enhancing our understanding about the three main stages of human carcinogenesis, namely initiation, promotion and progression, and how they contribute to the complexity of human cancer biology [45]. To this end, for example, ROS-mediated DNA damage plays a role in the initiation of carcinogenesis as well as in malignant transformation [8], [42] and thus, it may represent a major contributor in the pathogenesis of human carcinogenesis [7]. Finally, because human carcinogenesis is rather complex and multi-stage in origin, there are several different molecular mechanisms that contribute to its pathogenesis that include, but are not limited to, those that regulate gene expression and involve both genetic and epigenetic alterations. It would certainly be of major interest to identify such mechanism(s) in an attempt to elucidate their potential role as biomarkers for better cancer diagnostics and therapeutic strategies [30], [48].
Section snippets
Oxidative stress-induced genetic alterations in human carcinogenesis
The carcinogenicity of oxidative stress is primarily attributed to the genotoxicity of ROS in diverse cellular processes [7]. For example, hydroxyl radicals can react with pyrimidines and/or purines as well as chromatin proteins, resulting in base modifications and genomic instability respectively all of which can cause alterations in gene expression [42]. In addition, data have implicated ROS accumulation as being a common phenomenon in many cancer cells. Such accumulation can cause direct DNA
ROS-induced oxidative stress based epigenetic alterations in human carcinogenesis
In addition to causing genetic changes, ROS may lead to epigenetic alterations that affect the genome and play a key role in the development of human carcinogenesis [3]. More specifically, ROS production is associated with alterations in DNA methylation patterns [17], [54]. In particular, hydroxyl radical-induced DNA lesions (such as 8-hydroxyl-2-deoxyguanosine; 8-hydroxyguanine; 8-OHdG [56], [57], [58], [59], O6-methylguanine [60], [61] and single stranded DNA [62]) have all been shown to
Conclusions
Cancer is a rather complex, multifactorial and multistage disease with a number of molecular alterations involved in each stage (namely initiation, promotion and progression) of its development. Oxidative stress (a state of persistent generation of ROS overwhelming cellular defenses) has long been known to contribute to human carcinogenesis. Such contribution has been shown to regulate altered carcinogenic gene expression at the genetic as well the epigenetic level by very distinct mechanisms.
Conflict of interest
None.
Acknowledgments
This work was supported, in part, by the National Institutes of Health (Grant# P20RR17675), Centers of Biomedical Research Excellence (COBRE) and Layman Award form the University of Nebraska-Lincoln (Dr. Franco); a Marie Curie International Reintegration Grant within the 6th European Community Framework Program (MIRG-CT-2006-036585) (Dr. Pappa); and, in part, by the School of Community Health Sciences, a Junior Faculty Research Award from the University of Nevada-Reno and a Marie Curie
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