title: Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression.
abstract: The ability of cancer cells to survive and grow in anchorage- and serum-independent conditions is well correlated with their aggressiveness. Here, using a human whole-genome shRNA library, we identify TMIGD3 isoform1 (i1) as a factor that suppresses this ability in osteosarcoma (OS) cells, mainly by inhibiting NF-κB activity. Knockdown of TMIGD3 increases proliferation, tumour formation and metastasis of OS cells. Overexpression of TMIGD3 isoform1 (i1), but not isoform3 (i3) which shares a common C-terminal region, suppresses these malignant properties. Adenosine A3 receptor (A3AR) having an identical N-terminal region shows similar biological profiles to TMIGD3 i1. Protein expression of TMIGD3 and A3AR is lower in human OS tissues than normal tissues. Mechanistically, TMIGD3 i1 and A3AR commonly inhibit the PKA-Akt-NF-κB axis. However, TMIGD3 i1 only partially rescues phenotypes induced by A3AR knockdown, suggesting the presence of distinct pathways. Our findings reveal an unappreciated role for TMIGD3 i1 as a suppressor of NF-κB activity and OS progression.
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Wahl East 2005, Kansas City, Kansas 66160, USA.
authors.forename: Swathi V
authors.initials: SV
authors.lastname: Iyer
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Wahl East 2005, Kansas City, Kansas 66160, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Ranjan
authors.affiliation: Department of Internal Medicine, Icahn School of Medicine at Mount Sinai St Luke's-Roosevelt, New York 11575, USA.
authors.forename: Harold K
authors.initials: HK
authors.lastname: Elias
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Wahl East 2005, Kansas City, Kansas 66160, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Parrales
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Wahl East 2005, Kansas City, Kansas 66160, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Badal C
authors.initials: BC
authors.lastname: Roy
authors.affiliation: Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Shahid
authors.initials: S
authors.lastname: Umar
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Ossama W
authors.initials: OW
authors.lastname: Tawfik
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Wahl East 2005, Kansas City, Kansas 66160, USA.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C000628190:ADORA3 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D043684:Receptor, Adenosine A3; C000628147:TMIGD3 protein, human