Abstract
Nickel is a naturally occurring element found in the Earth’s crust and an International Agency for Research on Cancer (IARC)-classified human carcinogen. While low levels found in the natural environment pose a minor concern, the extensive use of nickel in industrial settings such as in the production of stainless steel and various alloys complicate human exposure and health effects. Notably, interactions with nickel macromolecules, primarily through inhalation, have been demonstrated to promote lung cancer. Mechanisms of nickel-carcinogenesis range from oxidative stress, DNA damage, and hypoxia-inducible pathways to epigenetic mechanisms. Recently, non-coding RNAs have drawn increased attention in cancer mechanistic studies. Specifically, nickel has been found to disrupt expression and functions of micro-RNAs and long-non-coding RNAs, resulting in subsequent changes in target gene expression levels, some of which include key cancer genes such as p53, MDM2, c-myc, and AP-1. Non-coding RNAs are also involved in well-studied mechanisms of nickel-induced lung carcinogenesis, such as the hypoxia-inducible factor (HIF) pathway, oxidative stress, DNA damage and repair, DNA hypermethylation, and alterations in tumor suppressors and oncogenes. This review provides a summary of the currently known epigenetic mechanisms involved in nickel-induced lung carcinogenesis, with a particular focus on non-coding RNAs.
Highlights
The number of ncRNAs studied in this area so far is limited, this review reveals a current state of knowledge and provides directions for future research in ncRNAs involved in nickel-induced carcinogenesis
Other than being an upstream regulator of maternally expressed gene 3 (MEG3) and many other long non-coding RNAs (lncRNAs) in carcinogenic signaling pathways, they can possibly be downstream of other genes; for example, TUG1 was found to be upregulated by p53 in lung cancer [108], indicating that TUG1 could be a potential lncRNA involved in the MEG3–p53 signaling pathway in nickel-induced lung carcinogenesis
Humans can be exposed to nickel from different sources and occupational exposure to nickel in nickel refineries and processing plants has been a big concern for workers and was reported to be related to lung cancer
Summary
Nickel is a commonly occurring metal on Earth, existing as both soluble and insoluble compounds in soil, fumes, and water. While nickel plays fundamental roles for plants, bacteria, archaea, and unicellular eukaryotes, there are no enzymes in the human body that require nickel to function. As a result, it is only biologically significant as a toxicant for humans [3]. Nickel sensitivity is a well-documented issue that affects millions of people. It is caused by triggering T-lymphocyte-driven delayed-type hypersensitivity reaction by Ni2+ , followed by leukocyte infiltration at the site of exposure [1]
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