Editing Malignant transformation (section)

==Induced by heavy metals==

The heavy metals [[cadmium]], [[arsenic]] and [[nickel]] are all carcinogenic when present above certain levels.<ref name="pmid26109463">{{cite journal |vauthors=Nawrot TS, Martens DS, Hara A, Plusquin M, Vangronsveld J, Roels HA, Staessen JA |title=Association of total cancer and lung cancer with environmental exposure to cadmium: the meta-analytical evidence |journal=Cancer Causes Control |volume=26 |issue=9 |pages=1281–8 |year=2015 |pmid=26109463 |doi=10.1007/s10552-015-0621-5 |s2cid=9729454 }}</ref><ref name="pmid24040994">{{cite journal |vauthors=Cohen SM, Arnold LL, Beck BD, Lewis AS, Eldan M |title=Evaluation of the carcinogenicity of inorganic arsenic |journal=Crit. Rev. Toxicol. |volume=43 |issue=9 |pages=711–52 |year=2013 |pmid=24040994 |doi=10.3109/10408444.2013.827152 |s2cid=26873122 }}</ref><ref name="pmid23314041">{{cite journal |vauthors=Bhattacharjee P, Banerjee M, Giri AK |title=Role of genomic instability in arsenic-induced carcinogenicity. A review |journal=Environ Int |volume=53 |pages=29–40 |year=2013 |pmid=23314041 |doi=10.1016/j.envint.2012.12.004 |bibcode=2013EnInt..53...29B |url=https://doaj.org/article/438d4ceca2e14b83bec36428473226c0 |url-access=subscription }}{{Dead link|date=April 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid23125218">{{cite journal |vauthors=Ji W, Yang L, Yuan J, Yang L, Zhang M, Qi D, Duan X, Xuan A, Zhang W, Lu J, Zhuang Z, Zeng G |title=MicroRNA-152 targets DNA methyltransferase 1 in NiS-transformed cells via a feedback mechanism |journal=Carcinogenesis |volume=34 |issue=2 |pages=446–53 |year=2013 |pmid=23125218 |doi=10.1093/carcin/bgs343 |doi-access=free }}</ref>

Cadmium is known to be carcinogenic, possibly due to reduction of DNA repair.  Lei et al.<ref name="pmid25729986">{{cite journal |vauthors=Lei YX, Lu Q, Shao C, He CC, Lei ZN, Lian YY |title=Expression profiles of DNA repair-related genes in rat target organs under subchronic cadmium exposure |journal=Genet. Mol. Res. |volume=14 |issue=1 |pages=515–24 |year=2015 |pmid=25729986 |doi=10.4238/2015.January.26.5 |doi-access=free }}</ref> evaluated five DNA repair genes in rats after exposure of the rats to low levels of cadmium.  They found that cadmium caused repression of three of the DNA repair genes: [[XRCC1]] needed for [[base excision repair]], [[Oxoguanine glycosylase|OGG1]] needed for base excision repair, and [[ERCC1]] needed for [[nucleotide excision repair]].  Repression of these genes was not due to methylation of their promoters.

Arsenic carcinogenicity was reviewed by Bhattacharjee et al.<ref name="pmid23314041"/>  They summarized the role of arsenic and its metabolites in generating oxidative stress, resulting in DNA damage.  In addition to causing DNA damage, arsenic also causes repression of several DNA repair enzymes in both the base excision repair pathway and the [[nucleotide excision repair]] pathway.  Bhattacharjee et al. further reviewed the role of arsenic in causing telomere dysfunction, mitotic arrest, defective apoptosis, as well as altered promoter methylation and miRNA expression.  Each of these alterations could contribute to arsenic-induced carcinogenesis.

Nickel compounds are carcinogenic and occupational exposure to nickel is associated with an increased risk of lung and nasal cancers.<ref name=Arita>{{cite journal |vauthors=Arita A, Muñoz A, Chervona Y, Niu J, Qu Q, Zhao N, Ruan Y, Kiok K, Kluz T, Sun H, Clancy HA, Shamy M, Costa M |title=Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects |journal=Cancer Epidemiol. Biomarkers Prev. |volume=22 |issue=2 |pages=261–9 |year=2013 |pmid=23195993 |pmc=3565097 |doi=10.1158/1055-9965.EPI-12-1011 }}</ref>  Nickel compounds exhibit weak mutagenic activity, but they considerably alter the transcriptional landscape of the DNA of exposed individuals.<ref name=Arita />  Arita et al.<ref name=Arita /> examined the [[peripheral blood mononuclear cell]]s of eight nickel-refinery workers and ten non-exposed workers.  They found  2756 differentially expressed genes with 770 up-regulated genes and 1986 down-regulated genes.  DNA repair genes were significantly over-represented among the differentially expressed genes, with 29 DNA repair genes repressed in the nickel-refinery workers and two over-expressed.  The alterations in gene expression appear to be due to epigenetic alterations of histones, methylations of gene promoters, and hypermethylation of at least microRNA miR-152.<ref name="pmid23125218"/><ref name="pmid24705264">{{cite journal |vauthors=Sun H, Shamy M, Costa M |title=Nickel and epigenetic gene silencing |journal=Genes  |volume=4 |issue=4 |pages=583–95 |year=2013 |pmid=24705264 |pmc=3927569 |doi=10.3390/genes4040583 |doi-access=free }}</ref>