title: Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells.
abstract: Osteosarcoma (OS) is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human OS. Vitamin D treatment of 143B OS cells induced significant and novel changes in the expression of genes that regulate: (a) inflammation and immunity; (b) formation of reactive oxygen species, metabolism of cyclic nucleotides, sterols, vitamins and mineral (calcium), quantity of gap junctions and skeletogenesis; (c) bone mineral density; and (d) cell viability of skeletal cells, aggregation of bone cancer cells and exocytosis of secretory vesicles. Ingenuity pathway analysis revealed significant reduction in Runx2 target genes such as fibroblast growth factor -1, -12 (FGF1andFGF12), bone morphogenetic factor-1 (BMP1), SWI/SNF related, matrix associated actin dependent regulator of chromatin subfamily a, member 4 (SMARCA4), Matrix extracellular phosphoglycoprotein (MEPE), Integrin, β4 (ITGBP4), Matrix Metalloproteinase -1, -28 (MMP1andMMP28), and signal transducer and activator of transcription-4 (STAT4) in vitamin D treated 143B OS cells. These genes interact with the inflammation, oxidative stress and membrane vesicle biogenesis gene networks. Vitamin D not only inhibited the expression of Runx2 target genesMMP1,MMP28and kallikrein related peptidase-7 (KLK7), but also migration and invasion of 143B OS cells. Vitamin D regulated Runx2 target genes or their products represent potential therapeutic targets and laboratory biomarkers for applications in translational oncology.
authors.affiliation: Division of Medical Clinical Oncology, The University of Kansas Medical Center, Kansas City, KS 66160, USA. Rama.Garimella@va.gov.|Departments of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA. Rama.Garimella@va.gov.|Orthopedic Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA. Rama.Garimella@va.gov.|Dietetics and Nutrition, The University of Kansas Medical Center, Kansas City, KS 66160, USA. Rama.Garimella@va.gov.|Midwest Biomedical Research Foundation-KCVAMC Affiliate, Kansas City, KS 64128, USA. Rama.Garimella@va.gov.|Hematology and Oncology, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA. Rama.Garimella@va.gov.|School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Rama.Garimella@va.gov.
authors.forename: Rama
authors.initials: R
authors.lastname: Garimella
authors.affiliation: Dietetics and Nutrition, The University of Kansas Medical Center, Kansas City, KS 66160, USA. surya.priyanka@gmail.com.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Tadikonda
authors.affiliation: Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA. otawfik@kumc.edu.
authors.forename: Ossama
authors.initials: O
authors.lastname: Tawfik
authors.affiliation: Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA. sgunewardena@kumc.edu.
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: Departments of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA. prowe@kumc.edu.|Kidney Institute, The University of Kansas Medical Center, Kansas City, KS 66160, USA. prowe@kumc.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Rowe
authors.affiliation: Division of Medical Clinical Oncology, The University of Kansas Medical Center, Kansas City, KS 66160, USA. Peter.Vanveldhuizen@va.gov.|Departments of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA. Peter.Vanveldhuizen@va.gov.|Sarah Cannon HCA Midwest Health Cancer Network, Overland Park, KS 66209, USA. Peter.Vanveldhuizen@va.gov.|Hematology and Oncology, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA. Peter.Vanveldhuizen@va.gov.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Veldhuizen
mesh_terms: D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism*; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D022161:Transport Vesicles / Q000235:genetics* / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D039663:Integrin beta4; C486579:MEPE protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; C493709:RUNX2 protein, human; D014157:Transcription Factors; D014815:Vitamins; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C082472:KLK7 protein, human; D007610:Kallikreins; D020782:Matrix Metalloproteinases; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Runx2; biomarkers; calcitriol; fibroblast growth factor 23; inflammation; membrane vesicle biogenesis; microarray; osteosarcoma; oxidative stress