Abstract
DNA repair inhibition has been described as an essential event leading to the initiation of carcinogenesis. In a previous study, we observed that the exposure to metal mixture induces changes in the miR-nome of the cells that was correlated with the sub-expression of mRNA involved in processes and diseases associated with metal exposure. From this analysis, one of the miRNAs that shows changes in its expression is miR-222, which is overexpressed in various cancers associated with exposure to metals. In silico studies showed that a possible target for the microRNA-222 could be Rad 51c, a gene involved in the double-stranded DNA repair. We could appreciate that up-regulation of miR-222 reduces the expression both gene and as a protein expression of Rad51c by RT-PCR and immunoblot, respectively. A luciferase assay was performed to validate Rad51c as miR-222 target. Neutral comet assay was performed in order to evaluate DNA double-strand breaks under experimental conditions. Here, we demonstrate that miR-222 up-regulation, directly regulates Rad51c expression negatively, and impairs homologous recombination of double-strand break DNA repair during the initiation stage of cell transformation. This inhibition triggers morphological transformation in a two-stage Balb/c 3T3 cell assay, suggesting that this small RNA acts as an initiator of the carcinogenesis process.
Highlights
The understanding of cancer has evolved dramatically during the last decades with the knowledge that cancer cells acquire their characteristics at different times during the development of cancer, in various microenvironments, through various mechanisms [1,2]
With respect to the basal values of RAD51c we found that the genetic expression with reference to the HPRT gene is 0.615± 0.15 and the protein expression with respect to Tubulin is 1.57 ± 0.33
We identified the possible direct binding of the miR-222 seed sequence on five different sites throughout the 3‘UTR of Rad51c mRNA using the miRWalk, microRNA and miRBase databases
Summary
The understanding of cancer has evolved dramatically during the last decades with the knowledge that cancer cells acquire their characteristics at different times during the development of cancer, in various microenvironments, through various mechanisms [1,2]. Genome instability is defined as an increased tendency of the genome to acquire genetic alterations [3]. It occurs when several processes involved in the maintenance and replication of the genome are dysfunctional or when there is an increasing exposure to carcinogens. The instability of the genome is an enabling feature that is causally associated with the acquisition of the distinctive characteristics of cancer.
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