title: PU.1 Is Identified as a Novel Metastasis Suppressor in Hepatocellular Carcinoma Regulating the miR-615-5p/IGF2 Axis.
abstract: Invasion and metastasis is the major cause of tumor recurrence, difficulty for cure and low survival rate. Excavating key transcription factors, which can regulate tumor invasion and metastasis, are crucial to the development of therapeutic strategies for cancers. PU.1 is a master hematopoietic transcription factor and a vital regulator in life. Here, we report that, compared to adjacent non-cancerous tissues, expression of PU.1 mRNA in metastatic hepatocellular carcinoma (HCC), but not primary HCC, was significantly down-regulated. In addition, levels of PU.1 mRNA in metastatic hepatoma cell lines MHCC97L and MHCC97H were much lower than in non-metastatic Hep3B cells. Transwell invasion assays after PU.1 siRNA transfection showed that the invasion of hepatoma cell lines was increased markedly by PU.1 knockdown. Oppositely, overexpression of PU.1 suppressed the invasion of these cells. However, knockdown and overexpression of PU.1 did not influence proliferation. Finally, we tried to explore the potential mechanism of PU.1 suppressing hepatoma cell invasion. ChIP-qPCR analysis showed that PU.1 exhibited a high binding capacity with miR-615-5p promoter sequence. Overexpression of PU.1 caused a dramatic increase of pri-, pre- and mature miR-615-5p, as well as a marked decrease of miR-615-5p target gene IGF2. These data indicate that PU.1 inhibits invasion of human HCC through promoting miR-615-5p and suppressing IGF2. These findings improve our understanding of PU.1 regulatory roles and provided a potential target for metastatic HCC diagnosis and therapy.
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China E-mail : liuxingw2014@163.com.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Song
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Chang
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Pan
authors.forename: Hong
authors.initials: H
authors.lastname: Zong
authors.forename: Qing-Xia
authors.initials: QX
authors.lastname: Fan
authors.forename: Liu-Xing
authors.initials: LX
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D007335:Insulin-Like Growth Factor II; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C035170:IGF2 protein, human; C534344:MIRN615 microRNA, human