title: TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.
abstract: Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.
authors.affiliation: 1] Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden [2] Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: P L
authors.initials: PL
authors.lastname: Chavali
authors.affiliation: Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
authors.forename: R K R
authors.initials: RK
authors.lastname: Saini
authors.affiliation: Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhai
authors.affiliation: Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Vizlin-Hodzic
authors.affiliation: 1] Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden [2] School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India.
authors.forename: S
authors.initials: S
authors.lastname: Venkatabalasubramanian
authors.affiliation: Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Johansson
authors.affiliation: 1] Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden [2] Molecular Biology Research Center, School of Biological Science and Technology, Central South University, Changsha, China.
authors.forename: Z-j
authors.initials: ZJ
authors.lastname: Zeng
authors.affiliation: Center for Molecular Pathology, Lund University, Skåne University Hospital, Malmö SE 20502, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Mohlin
authors.affiliation: Center for Molecular Pathology, Lund University, Skåne University Hospital, Malmö SE 20502, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Påhlman
authors.affiliation: 1] Program in Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1X8 [2] Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: L
authors.initials: L
authors.lastname: Hansford
authors.affiliation: 1] Program in Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1X8 [2] Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: D R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Funa
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000201:enzymology / Q000473:pathology*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C088601:NR2E1 protein, human; D050814:Octamer Transcription Factor-3; D057093:Orphan Nuclear Receptors; C494173:POU5F1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D020778:Matrix Metalloproteinase 2