MicroRNA‐9 inhibits growth and invasion of head and neck cancer cells and is a predictive biomarker of response to plerixafor, an inhibitor of its target CXCR4

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.

Epigenetic Modifications in Head and Neck Cancer

“…Recent studies show that HNSCC patients have a low expression of miR-9. Moreover, in HNSCC cell lines, knockdown of miR-9 causes an increased invasiveness, cell cycle progression, cellular proliferation, and colony formation, and targets the gene CXCR4, a discovery which may be useful in therapy (Hersi et al 2018). In NPC patients mir-9-3p is down-regulated, while its targets genes fibronectin 1 (FN1), β1 integrin (ITGB1), and α5 integrin (ITGAV) are upregulated.…”

miR-219a-5p represses migration and invasion of osteosarcoma cells via targeting EYA2

“…MiRNA (miRNAs), a class of small non-coding RNAs with $22 nucleotides in length, post-transcriptionally regulate gene expression by binding to the 3 0 UTR of the mRNA of their target gene [14,15]. Increasing evidence showed that miRNA, function as tumour suppressor genes or oncogenes, participates in the progression of various tumours including OS [16][17][18][19]. For example, Wu et al revealed that MiRNA-145-3p was reported as a tumour suppressor, inhibiting proliferation and induces apoptosis and autophagy of OS cell [20].…”

The Role of microRNAs in Epithelial Ovarian Cancer Metastasis

“…These studies also examined miR-9 expression in tissue samples, but observed a higher expression in serous EOC metastases compared to primary tumors [ 242 ] and lower expression in recurrent serous EOC tumors compared to primary EOC tissues [ 243 ]. The opposing effects of miR-9 also have been reported in other cancers, with varied targets and functional roles which are more likely dependent on tissue or cell type [ 310 , 311 , 312 ]. Similarly, miR-203 promoted OVCA429 and OVCA433 cell proliferation and migration in vitro, as well as tumor metastasis in vivo, by targeting pyruvate dehydrogenase B ( PDHB ) and the subsequent enhancement of glycolysis [ 118 ].…”