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MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer.
Koutsioumpa, Marina; Chen, Hsiao-Wang; O'Brien, Neil; Koinis, Filippos; Mahurkar-Joshi, Swapna; Vorvis, Christina; Soroosh, Artin; Luo, Tong; Issakhanian, Shawnt; Pantuck, Allan J; Georgoulias, Vassilis; Iliopoulos, Dimitrios; Slamon, Dennis J; Drakaki, Alexandra.
Afiliação
  • Koutsioumpa M; Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Chen HW; Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • O'Brien N; Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Koinis F; Laboratory of Tumor Cell Biology and Department of Medical Oncology, School of Medicine, University of Crete, Heraklion, Greece.
  • Mahurkar-Joshi S; Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Vorvis C; Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Soroosh A; Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Luo T; Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Issakhanian S; Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Pantuck AJ; Department of Urology, Institute of Urologic Oncology, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Georgoulias V; Laboratory of Tumor Cell Biology and Department of Medical Oncology, School of Medicine, University of Crete, Heraklion, Greece.
  • Iliopoulos D; Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Slamon DJ; Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California.
  • Drakaki A; Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California. adrakaki@mednet.ucla.edu.
Mol Cancer Ther ; 17(7): 1430-1440, 2018 07.
Article em En | MEDLINE | ID: mdl-29703843
ABSTRACT
Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas the MKAD-21 chemically modified antisense oligo against miR-21 dose-dependently blocked xenograft growth. I.v. administration of LNA miR-21 was more effective in suppressing tumor growth than was i.p. administration. Integration of computational and transcriptomic analyses in a panel of 28 bladder cancer lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21-induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A-ERK network in mice. Mol Cancer Ther; 17(7); 1430-40. ©2018 AACR.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Bexiga Urinária / Oligonucleotídeos Antissenso / MicroRNAs / Proteína Fosfatase 2 Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Bexiga Urinária / Oligonucleotídeos Antissenso / MicroRNAs / Proteína Fosfatase 2 Idioma: En Ano de publicação: 2018 Tipo de documento: Article