Abstract
Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality with up to 50% patient relapse. The lack of reliable tests to predict patient disease outcome highlights the need for predictive and/or prognostic biomarkers for patient tailored treatment. One class of biomarkers that has recently gained interest are microRNAs (miRNA). MiRNAs are small, non-coding molecules which regulate gene expression post transcriptionally. Our lab has performed miRNA expression profiling of a cohort of head and neck patients with known clinical outcomes. The results identified miR-9 to be downregulated in patients with poor treatment response, indicating its role as a potential biomarker in HNSCC.To investigate the role of miR-9 in HNSCC, the expression of miR-9 was investigated in human papilloma virus (HPV) positive HPV and negative HNSCC cell lines. We found the HPV negative HNSCC cell lines had low miR-9 expression. Conversely, miR-9 expression was found to be dramatically upregulated in HPV positive HNSCC cell lines compared to HPV negative cell lines. Overexpression of miR-9 in HPV negative HNSCC cell lines significantly decreased proliferation, colony formation, invasion and cell cycle progression with miR-9 knockdown having the opposite effect. Additionally, miR-9 expression was found to be induced by the HPV associated oncoprotein E6. E6 knockdown in HPV positive cells resulted in reduced miR-9 expression and increased colony formation capacity. Importantly, levels of CXCR4, a known target of miR-9, inversely correlated with miR-9 expression. CXCR4 overexpression increased proliferation, colony formation and cell cycle progression. Moreover, the addition of the CXCR4 specific ligand, CXCL12 to CXCR4 overexpressing and miR-9 knockdown cells enhanced the observed effects on proliferation, migration, colony formation and invasion. Whereas CXCR4 inhibition with plerixafor abrogated the oncogenic phenotype of CXCR4 overexpression and miR-9 knockdown.
Our data indicates that miR-9 functions as a tumour suppressive mircoRNA in HPV negative HNSCCs via CXCR4 repression in cell lines and in HPV positive HNSCCs, miR-9 is significant upregulated in tandem with E6 expression. MiR-9 and CXCR4 modulation significantly affect proliferation, colony formation and cell cycle progression in HPV negative HNSCC cell lines. These studies suggest the use of plerixafor as a potential therapeutic agent for HNSCC and miR-9 as a predictive biomarker in HPV negative HNSCC treatment.
| Date of Award | 1 Jul 2019 |
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| Original language | English |
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| Supervisor | Mahvash Tavassoli (Supervisor), Joop Gaken (Supervisor) & Teresa Guerrero Urbano (Supervisor) |