Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer.
TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients' biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene.
Université Paris-Sud 11, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; CNRS, Villejuif, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; Gustave Roussy, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805.
Giorgia
G
Urbinati
Université Paris-Sud 11, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; CNRS, Villejuif, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; Gustave Roussy, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805.
Hafiz Muhammad
HM
Ali
Université Paris-Sud 11, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; CNRS, Villejuif, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; Gustave Roussy, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; Laboratory of Experimental Cancer Research, Ghent University Hospital Building P7, De Pintelaan 185, B-9000 Gent, Belgium.
Quentin
Q
Rousseau
Institut Galien, UMR CNRS 8612, Université Paris-Sud 11, Faculté de pharmacie, 5 rue J. B. Clément, 92296 Châtenay-Malabry, France.
Hubert
H
Chapuis
Institut Galien, UMR CNRS 8612, Université Paris-Sud 11, Faculté de pharmacie, 5 rue J. B. Clément, 92296 Châtenay-Malabry, France.
Didier
D
Desmaële
Institut Galien, UMR CNRS 8612, Université Paris-Sud 11, Faculté de pharmacie, 5 rue J. B. Clément, 92296 Châtenay-Malabry, France.
Patrick
P
Couvreur
Université Paris-Sud 11, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; CNRS, Villejuif, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805; Gustave Roussy, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203, Villejuif, France-94805.
Liliane
L
Massaad-Massade
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004337:Drug Carriers; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013185:Squalene / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C547768:ADRA2A protein, human; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018341:Receptors, Adrenergic, alpha-2; C515553:TMPRSS2-ERG fusion protein, human; D013185:Squalene; D053148:Caspase 3