Abstract
Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality. Current treatment strategies are highly toxic and do not benefit over 50% of patients. There is therefore a crucial need for predictive and/or prognostic biomarkers to allow treatment stratification for individual patients. One class of biomarkers that has recently gained importance are microRNA (miRNA). MiRNA are small, noncoding molecules which regulate gene expression post‐transcriptionally. We performed miRNA expression profiling of a cohort of head and neck tumours with known clinical outcomes. The results showed miR‐9 to be significantly downregulated in patients with poor treatment outcome, indicating its role as a potential biomarker in HNSCC. Overexpression of miR‐9 in HNSCC cell lines significantly decreased cellular proliferation and inhibited colony formation in soft agar. Conversely, miR‐9 knockdown significantly increased both these features. Importantly, endogenous CXCR4 expression levels, a known target of miR‐9, inversely correlated with miR‐9 expression in a panel of HNSCC cell lines tested. Induced overexpression of CXCR4 in low expressing cells increased proliferation, colony formation and cell cycle progression. Moreover, CXCR4‐specific ligand, CXCL12, enhanced cellular proliferation, migration, colony formation and invasion in CXCR4‐overexpressing and similarly in miR‐9 knockdown cells. CXCR4‐specific inhibitor plerixafor abrogated the oncogenic phenotype of CXCR4 overexpression as well as miR‐9 knockdown. Our data demonstrate a clear role for miR‐9 as a tumour suppressor microRNA in HNSCC, and its role seems to be mediated through CXCR4 suppression. MiR‐9 knockdown, similar to CXCR4 overexpression, significantly promoted aggressive HNSCC tumour cell characteristics. Our results suggest CXCR4‐specific inhibitor plerixafor as a potential therapeutic agent, and miR‐9 as a possible predictive biomarker of treatment response in HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world with approximately 650 000 new cases diagnosed each year (Ferlay et al, 2010; Li et al, 2011; Raulf et al, 2014)
We demonstrate that miR-9 may be a potential biomarker for response of HNSCC to the CXCR4 inhibitor plerixafor
CXCL12 stimulation of scrambled control cells had no effect on colony formation whereas miR-9 knockdown cells had a significant increase in anoikis-resistant spheroid colonies after CXCL12 stimulation (P < 0.01, Fig. 5H). These results indicate that miR-9 knockdown similar to CXCR4 overexpression makes cells responsive to CXCL12 and strongly suggest that miR-9 tumour-suppressive effects are mediated via CXCR4 pathway
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world with approximately 650 000 new cases diagnosed each year (Ferlay et al, 2010; Li et al, 2011; Raulf et al, 2014). Genomewide miRNA profiling studies performed on various cancer types such as breast (Iorio et al, 2005), glioblastoma (Chan et al, 2005), hepatocellular carcinoma (Murakami et al, 2006) and lung (Yanaihara et al, 2006) amongst others (reviewed Calin and Croce, 2006) showed that miRNA profiles in cancers can be used to differentiate between disease subtypes and predict patient survival and treatment response (Lu et al, 2005). MiRNA expression profiling performed in lung cancer showed that specific miRNA signatures were able to discriminate between lung cancer and normal lung tissues and were able to differentiate between tumours with different prognosis (Yanaihara et al, 2006). MiRNA have potential diagnostic and prognostic roles as biomarkers in a variety of cancers including HNSCC (Hui et al, 2010, 2016; Summerer et al, 2015)
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