title: MiR-34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene.
abstract: MiR-34a-5p has been implicated in the tumorigenesis and progression of several types of cancer. However, the role of miR-34a-5p in osteosarcoma (OS) remains largely unknown. This study was performed in two multi-chemosensitive (G-292 and MG63.2) and two resistant (SJSA-1 and MNNG/HOS) OS cell lines. MiR-34a-5p promotes OS multi-chemoresistance via its repression of the Delta-like ligand 1 (DLL1) gene, the ligand of the Notch pathway, and thus negatively correlates with OS chemoresistance. The siRNA-mediated repression of the DLL1 gene suppressed cell apoptosis and de-sensitized G-292 and MG63.2 cells, while overexpression of DLL1 sensitized SJSA-1 and MNNG/HOS cells to drug-induced cell death. In agreement with the changes in the drug-induced cell death, the activity of the ATF2/ATF3/ATF4 signaling pathway was significantly altered by a forced reversal of miR-34a-5p or DLL1 levels in OS cells. DLL1 is a target of miR-34a-5p and negatively regulates the multi-chemoresistance of OS. This study suggested that miR-34a-5p, DLL1 and the ATF2/ATF3/ATF4 signaling pathway-associated genes are the potential diagnostic and/or therapeutic targets for an effective chemotherapy of OS. Our results also provide novel insights into the effective chemotherapy for OS patients.
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, West Branch of Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui, China.
authors.forename: Youguang
authors.initials: Y
authors.lastname: Pu
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, West Branch of Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Clinical Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, West Branch of Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui, China.|Department of Orthopedic Surgery, Anhui Cancer Hospital, West Branch of Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui, China.
authors.forename: Shanbao
authors.initials: S
authors.lastname: Cai
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C522425:MIRN34 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm