miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14

• Published in: Oncotarget Vol. 7; no. 26; pp. 40314 - 40328
• Main Authors: Zheng, Liduan, Jiao, Wanju, Mei, Hong, Song, Huajie, Li, Dan, Xiang, Xuan, Chen, Yajun, Yang, Feng, Li, Huanhuan, Huang, Kai, Tong, Qiangsong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 28.06.2016
• Subjects: Animals; Binding Sites; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Survival; Disease Models, Animal; Disease Progression; Human Umbilical Vein Endothelial Cells; Humans; Kruppel-Like Transcription Factors - metabolism; Male; Matrix Metalloproteinase 14 - metabolism; Mice; Mice, Nude; MicroRNAs - metabolism; Neoplasm Invasiveness; Promoter Regions, Genetic; Research Paper; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Treatment Outcome; gastric cancer; matrix metalloproteinase 14; transcriptional regulation; microRNA-337-3p; myeloid zinc finger 1
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9739

Matrix metalloproteinase 14 (MMP-14), a membrane-anchored MMP that promotes the tumorigenesis and aggressiveness, is highly expressed in gastric cancer. However, the transcriptional regulators of MMP-14 expression in gastric cancer still remain largely unknown. In this study, through mining computational algorithm programs and chromatin immunoprecipitation datasets, we identified adjacent binding sites of myeloid zinc finger 1 (MZF1) and miRNA-337-3p (miR-337-3p) within the MMP-14 promoter. We demonstrated that MZF1 directly bound to the MMP-14 promoter to facilitate its nascent transcription and expression in gastric cancer cell lines. In contrast, endogenous miR-337-3p suppressed the MMP-14 expression through recognizing its binding site within MMP-14 promoter. Mechanistically, miR-337-3p repressed the binding of MZF1 to MMP-14 promoter via recruiting Argonaute 2 and inducing repressive chromatin remodeling. Gain- and loss-of-function studies demonstrated that miR-337-3p suppressed the growth, invasion, metastasis, and angiogenesis of gastric cancer cells in vitro and in vivo through repressing MZF1-facilitated MMP-14 expression. In clinical specimens and cell lines of gastric cancer, MZF1 was highly expressed and positively correlated with MMP-14 expression. Meanwhile, miR-337-3p was under-expressed and inversely correlated with MMP-14 levels. miR-337-3p was an independent prognostic factor for favorable outcome of gastric cancer, and patients with high MZF1 or MMP-14 expression had lower survival probability. Taken together, these data indicate that miR-337-3p directly binds to the MMP-14 promoter to repress MZF1-facilitatd MMP-14 expression, thus suppressing the progression of gastric cancer.