Abstract
Inflammation is a potent inducer of tumorigenesis. Increased DNA damage or loss of genome integrity is thought to be one of the mechanisms linking inflammation and cancer development. It has been suggested that NF-κB-induced microRNA-146 (miR146a) may be a mediator of the inflammatory response. Based on our initial observation that miR146a overexpression strongly increases DNA damage, we investigated its potential role as a modulator of DNA repair. Here, we demonstrate that FANCM, a component in the Fanconi Anemia pathway, is a novel target of miR146a. miR146a suppressed FANCM expression by directly binding to the 3′ untranslated region of the gene. miR146a-induced downregulation of FANCM was associated with inhibition of FANCD2 monoubiquitination, reduced DNA homologous recombination repair and checkpoint response, failed recovery from replication stress, and increased cellular sensitivity to cisplatin. These phenotypes were recapitulated when miR146a expression was induced by overexpressing the NF-κB subunit p65/RelA or Helicobacter pylori infection in a human gastric cell line; the phenotypes were effectively reversed with an anti-miR146a antagomir. These results suggest that undesired inflammation events caused by a pathogen or over-induction of miR146a can impair genome integrity via suppression of FANCM.
Highlights
Chronic inflammation is believed to be a causative factor for tumorigenesis
We demonstrated that Fanconi anemia group M protein (FANCM) is a direct target of miR146a
We showed that miR146a overexpression disrupted the several known FANCM-dependent processes, such as: Fanconi anemia complementation group D2 (FANCD2) monoubiquitination/foci formation, the FANCM-mediated checkpoint response, replication fork stability, and cellular resistance to cisplatin and HU. miR146a overexpression led to the reduced RAD51 foci formation and increased double-strand www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget break formation, these phenotypes could be attributed to both impaired FANCD2 activation as well as BRCA1 expression
Summary
Chronic inflammation is believed to be a causative factor for tumorigenesis. It is a pleiotropic transcription factor that can exert profound effects on the cellular immune state by coordinating the expression of numerous downstream targets [2, 3]. MicroRNA-146a (miR146a), recognized as a gene targeted by NF-κB, has been implicated in a variety of cellular functions, in pathological conditions, such as inflammation and cancer [4,5,6]. Chronic inflammation caused by a variety of pathogens such as Helicobacter pylori (H. pylori) can presumably www.impactjournals.com/oncotarget induce the long term expression of NF-κB and miR146a [7,8,9]. This study investigated the potential influence of H. pylori infection, activation of NF-κB, and miR146a on cellular genome integrity and tumorigenesis
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