Abstract
BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC.MethodsTo evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target.ResultsOur data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation.ConclusionsThese results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide
Results miR-96-5p upregulation correlates with TP53 status and predicts local recurrence development in HNSCC patients In our previous studies, we have identified TP53-mutation associated alterations of miRNAs expression in HNSCC tissues [14, 15, 24]
We demonstrated that the expression of a specific TP53-mutation associated four-miRNAs signature predicts local recurrence insurgence in tumors and matched histologically tumor-free peritumor tissues from HNSCC patients [14, 24]. miR-96-5p was included in this signature and because its oncogenic activity in HNSCC cells has not been deeply characterized yet, here we decided to focus our attention on this miRNA
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. Head and neck cancers are the sixth leading cancer worldwide and they are represented mainly by the squamous cell carcinoma (HNSCC) occurring in the oral cavity, pharynx, or larynx [1,2,3,4] They are typically characterized by a high incidence of local recurrences, which are the most common cause of death in HNSCC patients, taking place in 60% of cases [5, 6]. The TNM staging system, used to classify HNSCC patients, does not adequately address the molecular heterogeneity of HNSCC tumors and patients with the same TNM stages have a heterogeneous response to therapy [9] This indicates the need to obtain a more detailed molecular characterization in order to improve our understanding of radio and chemo-resistance mechanisms, to identify biomarkers for early detection of local recurrence and treatment response. One of the emerging miRNAs as oncogene and biomarker in HNSCC is miR-96-5p [22, 23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
