Abstract
MicroRNA controls cancer invasion by governing the expression of gene regulating migration and invasion. Here, we reported a novel regulatory pathway controlled by miR-744-3p, which enhanced expression of matrix metallopeptidase 9 (MMP-9) in laryngeal squamous cell carcinoma (LSCC). We profiled the differential micoRNA expression pattern in LSCC cell lines and normal epithelial cultures derived from the head and neck mucosa using microRNA microarray. MiR-7-1-3p, miR-196a/b and miR-744-3p were expressed differentially in the LSCC cell lines. Subsequent validation using real-time PCR revealed that high miR-744-3p level was positively correlated with regional lymph node metastasis of LSCC. Real-time cellular kinetic analysis showed that suppressing miR-744-3p could inhibit migration and invasion of LSCC cell lines and reduce the number of lung metastatic nodules in nude mice modules. In silico analysis revealed that miR-744-3p targeted 2 distinct signaling cascades which eventually upregulated MMP-9 expression in LSCC. First, miR-744-3p could suppress programmed cell death 4 (PDCD4), a direct suppressor of NF-κB (p65). PDCD4 could also prevent AKT activation and suppress MMP-9 expression. Further, suppressing miR-744-3p expression could restore phosphatase and tensin homolog (PTEN) expression. PTEN could inhibit AKT activation and inhibit MMP-9 expression in LSCC cells. The results revealed that suppressing miR-744-3p was effective to inhibit LSCC metastasis by inactivating AKT/mTOR and NF-κB (p65) signaling cascade. Targeting miR-744-3p could be a valuable therapeutic intervention to suppress the aggressiveness of LSCC.
Highlights
Cancer of the larynx originating from the head and neck region is the second most common upperaerodigestive cancer [1, 2]
The association between high miR-744-3p expression and regional lymph node positive suggested that miR-744-3p could possibly play a part in controlling laryngeal squamous cell carcinoma (LSCC) migration and invasion
Our results confirmed that the expression level of miR-744-3p could have a functional impact on the migration and invasion propensity of LSCC cells
Summary
Cancer of the larynx originating from the head and neck region is the second most common upperaerodigestive cancer [1, 2]. Laryngeal squamous cell carcinoma (LSCC) is the major form. Despite the advances of cancer treatment in the past few decades, the prognosis of LSCC patients remains poor without significant improvement [3]. Recent data reveals that the morbidity and mortality associates with LSCC are increasing in recent year [3, 4]. Local invasion and metastatic spread of cancer cells is one of the main causes of death in LSCC patients [5]. Laryngeal cancer patients present with cervical lymph node involvement have poorer disease free interval and overall survival [6]. Given that the key cellular and molecular mechanisms resulting in LSCC migration and invasion are less understood, investigation on the underlying mechanism will be clinically beneficial for developing molecular targeting therapy
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