Oncotarget

Research Papers:

MicroRNA 744-3p promotes MMP-9-mediated metastasis by simultaneously suppressing PDCD4 and PTEN in laryngeal squamous cell carcinoma

John Zeng-Hong Li, Wei Gao, Wen-Bin Lei, Jing Zhao, Jimmy Yu-Wai Chan, William Ignace Wei, Wei-Kuen Ho and Thian-Sze Wong _

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Oncotarget. 2016; 7:58218-58233. https://doi.org/10.18632/oncotarget.11280

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Abstract

John Zeng-Hong Li1,2, Wei Gao1, Wen-Bin Lei3, Jing Zhao3, Jimmy Yu-Wai Chan1, William Ignace Wei1, Wei-Kuen Ho1, Thian-Sze Wong1

1Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong

2Department of Otolaryngology, The First People's Hospital of Foshan, Foshan, People’s Republic of China

3Department of Otolaryngology, The First Affiliated Hospital of Sun Yet-Sen University, Guangdong, People’s Republic of China

Correspondence to:

Thian-Sze Wong, email: [email protected]

Keywords: miR-744-3p, metastasis, PDCD4, PTEN, laryngeal squamous cell carcinoma

Received: September 22, 2015     Accepted: August 08, 2016     Published: August 13, 2016

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.


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