Abstract
Defective DNA damage response (DDR) is frequently associated with tumorigenesis. Abrogation of DDR leads to genomic instability, which is one of the most common characteristics of human cancers. TP53 mutations with gain-of-function activity are associated with tumors under high replicative stress, high genomic instability, and reduced patient survival. The BRCA1 and RAD17 genes encode two pivotal DNA repair proteins required for proper cell-cycle regulation and maintenance of genomic stability. We initially evaluated whether miR-205-5p, a microRNA (miRNA) highly expressed in head and neck squamous cell carcinoma (HNSCC), targeted BRCA1 and RAD17 expression. We found that, in vitro and in vivo, BRCA1 and RAD17 are targets of miR-205-5p in HNSCC, leading to inefficient DNA repair and increased chromosomal instability. Conversely, miR-205-5p downregulation increased BRCA1 and RAD17 messenger RNA (mRNA) levels, leading to a reduction in in vivo tumor growth. Interestingly, miR-205-5p expression was significantly anti-correlated with BRCA1 and RAD17 targets. Furthermore, we documented that miR-205-5p expression was higher in tumoral and peritumoral HNSCC tissues than non-tumoral tissues in patients exhibiting reduced local recurrence-free survival. Collectively, these findings unveil miR-205-5p’s notable role in determining genomic instability in HNSCC through its selective targeting of BRCA1 and RAD17 gene expression. High miR-205-5p levels in the peritumoral tissues might be relevant for the early detection of minimal residual disease and pre-cancer molecular alterations involved in tumor development.
Highlights
The exogenous and endogenous damage of DNA leads to the destruction of the cell’s genomic build
We previously reported that BRCA1 and RAD17 genes were transcriptionally repressed by the oncogenic mutant p53/E2F4 protein complex which was recruited onto the E2F4 consensus sequences within the BRCA1 and RAD17 promoter regions [20]
To shed light on additional mechanisms via which DNA repair activity was inhibited in head and neck squamous cell carcinoma (HNSCC), we focused our attention on miR-205-5p
Summary
The exogenous and endogenous damage of DNA leads to the destruction of the cell’s genomic build. In these cases, eukaryotic cells activate a complex DNA damage response (DDR) that allows them to correctly activate cell-cycle checkpoints and implement DNA repair mechanisms [1]. Chromosomal instability (CIN) is common in many types of cancer and can be caused by replication stress, non-conservative mitosis, telomere instability, and defective repair of double-stranded DNA breaks (DSBs) [1,2]. DSB repair can be done via non-homologous end-joining (NHEJ) or homologous recombination (HR). DSB is involved in tumor development as it facilitates the loss of tumor suppressors and the activation of oncogenic pathways.
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