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A Model for Perineural Invasion in Head and Neck Squamous Cell Carcinoma
Published on: January 5, 2017
The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas
Fabio Valenti1, Andrea Sacconi1, Federica Ganci1
1Oncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.
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.
Insights
MicroRNA-205-5p promotes head and neck cancer by targeting DNA repair genes BRCA1 and RAD17, increasing genomic instability. Lowering this microRNA reduced tumor growth, suggesting therapeutic potential.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Defective DNA damage response (DDR) is linked to cancer development and genomic instability.
- TP53 mutations and genomic instability correlate with poor patient survival in certain cancers.
- BRCA1 and RAD17 are crucial DNA repair proteins for maintaining genomic stability.
Purpose of the Study:
- To investigate if miR-205-5p targets BRCA1 and RAD17 in head and neck squamous cell carcinoma (HNSCC).
- To determine the role of miR-205-5p in DNA repair, genomic instability, and tumor growth in HNSCC.
- To explore the potential of miR-205-5p as a biomarker for HNSCC detection and prognosis.
Main Methods:
- In vitro and in vivo experiments to assess miR-205-5p targeting of BRCA1 and RAD17.
- Analysis of BRCA1 and RAD17 mRNA levels in response to miR-205-5p modulation.
- Correlation analysis between miR-205-5p expression and BRCA1/RAD17 levels in HNSCC tissues.
- Evaluation of miR-205-5p expression in tumoral, peritumoral, and non-tumoral tissues.
Main Results:
- BRCA1 and RAD17 were confirmed as direct targets of miR-205-5p in HNSCC.
- miR-205-5p overexpression led to reduced BRCA1/RAD17 expression, inefficient DNA repair, and increased chromosomal instability.
- Downregulation of miR-205-5p increased BRCA1/RAD17 levels and inhibited tumor growth.
- miR-205-5p expression was inversely correlated with BRCA1 and RAD17 levels.
- Higher miR-205-5p levels were observed in HNSCC tissues compared to normal tissues, correlating with poorer survival.
Conclusions:
- miR-205-5p drives genomic instability in HNSCC by targeting BRCA1 and RAD17.
- Modulating miR-205-5p offers a potential therapeutic strategy for HNSCC.
- Elevated miR-205-5p in peritumoral tissue may aid in early detection of minimal residual disease and pre-cancerous changes.
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