title: miRNA-558 promotes tumorigenesis and aggressiveness of neuroblastoma cells through activating the transcription of heparanase.
abstract: Heparanase (HPSE) is the endogenous endoglycosidase that degrades heparan sulfate proteoglycans and promotes the tumor growth, invasion, metastasis and angiogenesis. Our previous studies have shown that HPSE is highly expressed in neuroblastoma (NB), the most common extracranial solid tumor in childhood. However, the underlying regulatory mechanisms remain largely unknown. In this study, we identified one binding site of microRNA-558 (miR-558) within the HPSE promoter. In NB tissues and cell lines, miR-558 was up-regulated and positively correlated with HPSE expression. Gain- and loss-of-function studies demonstrated that miR-558 facilitated the transcript and protein levels of HPSE and its downstream gene, vascular endothelial growth factor, in NB cell lines. In addition, miR-558 enhanced the promoter activities of HPSE, and these effects were abolished by the mutation of the miR-558-binding site. Mechanistically, miR-558 induced the enrichment of the active epigenetic marker and RNA polymerase II on the HPSE promoter in NB cells in an Argonaute 1-dependent manner, which was abolished by repressing the miR-558-promoter interaction. Knockdown of endogenous miR-558 decreased the growth, invasion, metastasis and angiogenesis of NB cells in vitro and in vivo. In contrast, over-expression of miR-558 promoted the growth, invasion, metastasis and angiogenesis of SH-SY5Y and SK-N-SH cells. Restoration of HPSE expression prevented the NB cells from changes in these biological features induced by knockdown or over-expression of miR-558. These data indicate that miR-558 induces the transcriptional activation of HPSE via the binding site within promoter, thus facilitating the tumorigenesis and aggressiveness of NB.
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Pathology, Clinical Center of Human Genomic Research and.
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Pu
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery.
authors.forename: Shiwang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.affiliation: Clinical Center of Human Genomic Research and.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Pediatric Surgery, Clinical Center of Human Genomic Research and qs_tong@hotmail.com.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015533:Transcriptional Activation; D014162:Transfection; D047368:Tumor Burden / Q000235:genetics; D015854:Up-Regulation; D000099175:Heparanase
chemical_list: D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors; D005966:Glucuronidase; D035683:MicroRNAs; D000099175:Heparanase; C115848:AGO1 protein, human; C000603689:MIRN-558 microRNA, human