title: MicroRNA 744-3p promotes MMP-9-mediated metastasis by simultaneously suppressing PDCD4 and PTEN in laryngeal squamous cell carcinoma.
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.
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|Department of Otolaryngology, The First People's Hospital of Foshan, Foshan, People's Republic of China.
authors.forename: John Zeng-Hong
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of Sun Yet-Sen University, Guangdong, People's Republic of China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Lei
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of Sun Yet-Sen University, Guangdong, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Jimmy Yu-Wai
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: William Ignace
authors.initials: WI
authors.lastname: Wei
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Wei-Kuen
authors.initials: WK
authors.lastname: Ho
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Thian-Sze
authors.initials: TS
authors.lastname: Wong
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D007830:Larynx / Q000473:pathology; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008207:Lymphatic Metastasis; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C569733:MIRN744 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; C498143:RELA protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051996:Transcription Factor RelA; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: PDCD4; PTEN; laryngeal squamous cell carcinoma; metastasis; miR-744-3p