Oncogenomic disruptions in arsenic-induced carcinogenesis

Abstract

Chronic exposure to arsenic affects more than 200 million people worldwide, and has been associated with many adverse health effects, including cancer in several organs. There is accumulating evidence that arsenic biotransformation, a step in the elimination of arsenic from the human body, can induce changes at a genetic and epigenetic level, leading to carcinogenesis. At the genetic level, arsenic interferes with key cellular processes such as DNA damage-repair and chromosomal structure, leading to genomic instability. At the epigenetic level, arsenic places a high demand on the cellular methyl pool, leading to global hypomethylation and hypermethylation of specific gene promoters. These arsenic-associated DNA alterations result in the deregulation of both oncogenic and tumour-suppressive genes. Furthermore, recent reports have implicated aberrant expression of non-coding RNAs and the consequential disruption of signaling pathways in the context of arsenic-induced carcinogenesis. This article provides an overview of the oncogenomic anomalies associated with arsenic exposure and conveys the importance of non-coding RNAs in the arsenic-induced carcinogenic process.

Keywords: arsenic; cancer; epigenetics; genetics; non-coding RNA.

Figure 1. Health effects associated with chronic exposure to inorganic arsenic from contaminated drinking water

Levels of iAs in drinking water near the maximum threshold of 10μg/L can lead to the onset of many diseases in a number of areas in the body. Cancer is a particularly prevalent disease resulting from chronic arsenic exposure, represented in italics.

Figure 2. The biotransformation of inorganic arsenic and mechanisms of arsenic-induced carcinogenesis

The reduction, oxidation and methylation of pentavalent arsenic (As^V, green pentagon) occurs after cellular intake via membrane transport proteins (blue cylinder). Mitochondrial ATP synthase (purple) conjugates As^V with ADP, which is then reduced by the electron donor glutathione (GSH) to produce As^III (blue trapezoid), a more cytotoxic form of arsenic. In order for excretion, As^III is methylated with methyl groups donated by S-adenosylmethionine methyltransferase (SAM). These methylated arsenic species (MMA, DMA; yellow) all have carcinogenic potential through the induction (red lightning bolt) of a number of genomic and epigenetic effects (red gears), culminating in transcriptomic changes and generalized genomic instability.

Figure 3. Number of publications relating genetics and epigenetics to arsenic exposure

Search was performed within EndNote (Version 7, Thomson Reuters) and manually filtered. Number of publications are based on a United States National Library of Medicine PubMed search using the terms “arsenic AND genetic” (blue line), “arsenic AND epigenetic” (red line), “arsenic AND miRNA OR microRNA” (green line), or “arsenic AND lncRNA OR lincRNA OR long non-coding RNA” (purple line). 2016 publications were not included in the search, and annual (Jan 1-Dec 31) date limitations were used.

Figure 4. Circular representation of DNA copy-number alterations (CNAs) in lung squamous cell carcinomas

Each chromosome of the human genome (hg19) is represented in the outer circle. Only lung squamous cell carcinomas were considered for this analysis, since this is the histological subtype more strongly associated with arsenic exposure. In arsenic exposed patients, there is an unusually high frequency of lung SqCC among never smokers, while this subtype is almost exclusively associated with smokers in non-arsenic related lung SqCC. CNAs detected in lung SqCCs arsenic-exposed, non-smoker patients (red, n=10), arsenic-exposed, smokers (blue, n=12) and non-arsenic exposed, smokers (dark grey, n=20) are shown. On each chart, the frequency of DNA gains among cases is shown above the black line indicating absence of alterations, while the frequency of DNA losses are shown below. Overall, the number of alterations observed in arsenic-exposed, non-smokers lung SqCCs are significantly lower than smokers. Interestingly, one of the most characteristic alterations described in lung SqCC (DNA gains 3q and 5p) exhibits a remarkable similarity among smokers, regardless of arsenic exposure status, while a low frequency of alterations is observed among non-smokers, arsenic-exposed patients (segments A and B).

Figure 5. Network interactions between deregulated miRNAs and their predicted targets upon arsenic exposure

miRNAs shown to be deregulated after exposure to arsenic and described in this review were inputted into miRDIP for gene target prediction, using the thresholds of the top 1% of mRNA transcripts predicted by at least 3 different prediction databases. NAViGaTOR [178] was used to visualize the interactions between these miRNAs and their predicted mRNA targets. miRNAs deregulated after exposure to arsenic are depicted by coloured square nodes, while their predicted mRNA targets are represented by circular nodes. Edges indicate predicted miRNA/mRNA interactions and are coloured according to the identity of the selected miRNA. The mRNA-target nodes are coloured as per to their association with Gene Ontology terms. Certain mRNAs appear to be shared by several of the miRNAs identified (i.e. FGF4, AAK1, CHD7, HPDL etc.), representing possible important cellular functions that are affected by arsenic exposure, such as cellular fate and energy production.

Figure 6. Mechanisms of piRNA action

piRNAs associate with PIWI proteins in the cytoplasm, forming a ribonucleoprotein effector complex that is able to recognize and bind to complementary target sequences on DNA both in the cytoplasm and nucleus (panel A). When bound to the target sequence, piRNA-PIWI complexes can recruit epigenetic remodeling machinery (panels B and D) to either repress transcription through DNA methylation (panel C) or activate transcription through DNA acetylation or methylation removal (Panel E).