Abstract
MiR-34a is a well-known tumor metastasis inhibitor, but only a few target genes involved in metastasis have been identified. In HNSCC, the role of miR-34a in metastasis has not been fully elaborated, and the target gene of miR-34a is still blind. Here we addressed that, the relative lower expression of miR-34a is associated with HNSCC lymphatic metastasis. HNSCC metastasis was found to be strongly suppressed in vitro and in vivo by over-expressing miR-34a. In order to screen the possible target genes of miR-34a in HNSCC, a microarray-based differential mRNA profiling mediated by miR-34a over-expression was performed, and AREG was identified as a pivotal target. We demonstrated that the mRNA and protein levels of AREG were greatly reduced when forcing miR-34a expression. The correlation between AREG mRNA levels and HNSCC metastatic phenotype was also significant in HNSCC tissues (p < 0.01). Moreover, the results of luciferase assay provided the further evidence that miR-34a degraded AREG mRNA through targeting the 3'-UTR site. Restoration of AREG expression partially rescued miR-34a-mediated cell invasion defects in vivo and in vitro. Additionally, Over-expressing miR-34a greatly reduced EGFR and uPA, which were reversed by re-expression of AREG. Taken together, these findings indicate that miR-34a targets AREG, and is essential in inhibition of HNSCC metastasis.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is an invasive epithelial neoplasm with a propensity to early and extensive lymph node metastases [1]
In order to screen the possible target genes of miR-34a in HNSCC, a microarray-based differential mRNA profiling mediated by miR-34a over-expression was performed, and AREG was identified as a pivotal target
These findings indicate that miR-34a targets AREG, and is essential in inhibition of HNSCC metastasis
Summary
Head and neck squamous cell carcinoma (HNSCC) is an invasive epithelial neoplasm with a propensity to early and extensive lymph node metastases [1]. Because of the multifactorial etiopathogenesis of HNSCC, the development of multimodality treatments is suboptimal in recurrent and/or metastatic disease and only half of the patients are alive in 5 years [3, 4]. Despite of the advances in primary HNSCC treatment, the lack of good molecular targets and biological heterogeneity hinder the development of gene therapy in metastatic HNSCC [4, 5]. The investigation of new biomarkers, based on the biology of the disease, is of major importance to HNSCC metastasis. It has been suggested that miRNAs are capable to modulate a number of oncogenes or tumor suppressor genes and participate in the regulation of malignant transformation, progression of disease, and metastatic colonization [8]. A group of www.impactjournals.com/oncotarget microRNAs have been identified altered in HNSCC and served as biomarkers for tumorigenesis, clinical prognosis, and metastasis [9,10,11]
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