The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas
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. <i>TP53</i> mutations with gain-of-function activity are associated with tumors under high re...
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| Format: | Article |
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MDPI AG
2019-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/9/1347 |
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| author | Fabio Valenti Andrea Sacconi Federica Ganci Giuseppe Grasso Sabrina Strano Giovanni Blandino Silvia Di Agostino |
| author_facet | Fabio Valenti Andrea Sacconi Federica Ganci Giuseppe Grasso Sabrina Strano Giovanni Blandino Silvia Di Agostino |
| author_sort | Fabio Valenti |
| collection | DOAJ |
| description | 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. <i>TP53</i> mutations with gain-of-function activity are associated with tumors under high replicative stress, high genomic instability, and reduced patient survival. The <i>BRCA1</i> and <i>RAD17</i> 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 <i>BRCA1</i> and <i>RAD17</i> expression. We found that, in vitro and in vivo, <i>BRCA1</i> and <i>RAD17</i> are targets of miR-205-5p in HNSCC, leading to inefficient DNA repair and increased chromosomal instability. Conversely, miR-205-5p downregulation increased <i>BRCA1</i> and <i>RAD17</i> messenger RNA (mRNA) levels, leading to a reduction in in vivo tumor growth. Interestingly, miR-205-5p expression was significantly anti-correlated with <i>BRCA1</i> and <i>RAD17</i> 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 <i>BRCA1</i> and <i>RAD17</i> 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. |
| first_indexed | 2024-03-12T10:21:27Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:21:27Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2e531be832524ffca965979a7e75ebc22023-09-02T10:05:37ZengMDPI AGCancers2072-66942019-09-01119134710.3390/cancers11091347cancers11091347The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell CarcinomasFabio Valenti0Andrea Sacconi1Federica Ganci2Giuseppe Grasso3Sabrina Strano4Giovanni Blandino5Silvia Di Agostino6Oncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyOncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyOncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyOncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyMolecular Chemoprevention Group, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyOncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyOncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyDefective 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. <i>TP53</i> mutations with gain-of-function activity are associated with tumors under high replicative stress, high genomic instability, and reduced patient survival. The <i>BRCA1</i> and <i>RAD17</i> 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 <i>BRCA1</i> and <i>RAD17</i> expression. We found that, in vitro and in vivo, <i>BRCA1</i> and <i>RAD17</i> are targets of miR-205-5p in HNSCC, leading to inefficient DNA repair and increased chromosomal instability. Conversely, miR-205-5p downregulation increased <i>BRCA1</i> and <i>RAD17</i> messenger RNA (mRNA) levels, leading to a reduction in in vivo tumor growth. Interestingly, miR-205-5p expression was significantly anti-correlated with <i>BRCA1</i> and <i>RAD17</i> 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 <i>BRCA1</i> and <i>RAD17</i> 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.https://www.mdpi.com/2072-6694/11/9/1347miRNAHNSCCDNA repairgenomic instabilitymutant p53 |
| spellingShingle | Fabio Valenti Andrea Sacconi Federica Ganci Giuseppe Grasso Sabrina Strano Giovanni Blandino Silvia Di Agostino The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas Cancers miRNA HNSCC DNA repair genomic instability mutant p53 |
| title | The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas |
| title_full | The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas |
| title_fullStr | The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas |
| title_full_unstemmed | The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas |
| title_short | The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas |
| title_sort | mir 205 5p brca1 rad17 axis promotes genomic instability in head and neck squamous cell carcinomas |
| topic | miRNA HNSCC DNA repair genomic instability mutant p53 |
| url | https://www.mdpi.com/2072-6694/11/9/1347 |
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