RESUMO
Taurine upregulated gene 1 (TUG1) has been implicated in the onset and progression of various malignancies. The current study aimed to evaluate the biological function and potential mechanisms of TUG1 in multiple myeloma (MM) progression. TUG1 knockdown in MM cells was investigated in vitro and in vivo to evaluate the role of TUG1. We also predicted the transcription factor (TF) that bound to TUG1 together with the downstream target genes of the TUG1-TF interaction, and evaluated the regulatory mechanism of TUG1 in cell assays. TUG1 knockdown reduced the cell's proliferative and migratory capabilities while increasing apoptosis and bortezomib sensitivity in vitro and inhibiting tumorigenesis in vivo. TUG1 was found in the nucleus of MM cells and was found to be positively regulated by the TF-YY1. Further in vitro mechanistic investigations indicated that the YY1-TUG1 complex targeted YOD1 to regulate MM progression.
Assuntos
MicroRNAs , Mieloma Múltiplo , RNA Longo não Codificante , Humanos , Apoptose/genética , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , RNA Longo não Codificante/genética , Taurina , Tioléster Hidrolases/genética , Fator de Transcrição YY1/genéticaRESUMO
A proliferation-inducing ligand (APRIL) is a key cell proliferation-regulatory molecule and have been investigated well enough in immunity regulation and a few of immune diseases. APRIL can stimulate tumor cell growth and is up-expressed in cancer tissues, especially in CRC (colorectal cancer). However, whether inhibition of APRIL can regulate tumor-relative genes expression in vivo and subsequently ameliorate the pathological progress of CRC remains obscure. To address this question, we developed a novel negative lipidoid nanoparticles (NLNs) encapsulating small interference RNA (siRNA) for selectively silencing APRIL in the parenchyma of CRC focus in vivo, which uptake proceeded through a lipid raft endocytotic pathway. Local enema delivery of APRIL-NLNs silenced APRIL in CRC cells and animal models, and then ameliorated experimentally the progress of CRC by suppressing CRC cell proliferation, metastasis, and apoptosis-related cytokine expression and did not affect the function of liver and kidneys and not trigger the immune response of CRC models. This study reveals APRIL to be a potential anti-CRC target by in vivo experiments, and suggests that the application of similar modes of siRNA delivery may be feasible in other therapeutic settings.
Assuntos
Neoplasias Colorretais/prevenção & controle , Sistemas de Liberação de Medicamentos , Enema , Lipídeos/química , Nanopartículas/química , RNA Interferente Pequeno/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Apoptose , Western Blotting , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The nontoxic, targeted and effective delivery of nucleic acid drugs remains an important challenge for clinical development. Here, we describe a novel negative lipidoid nanoparticle delivery system, providing entrapment-based transfection agents for local delivery of siRNA to the colorectal cancer focus. The delivery system was synthesized with lipidoid material 98N12-5(1), mPEG2000-C12/C14 glyceride and cholesterol at a desired molar ratio to realize the anionic surface charge of particles, which could alleviate to a larger degree the inflammatory response and immune stimulation of the organism, embodying dramatic biocompatibility. In particular, mPEG2000-C12/C14 glyceride was selected to ameliorate the stability of the delivery system and protection of nucleic acids by extending the tail length of the carbons, crucial also to neutralize the positive charge of 98N12-5(1) to form a resultant anionic particle. In vivo experiments revealed that a particle size of 90 nm perfectly realized a passive target in a size-dependent manner and did not affect the function of the liver and kidneys by a local delivery method, enema. We clarified that the uptake of negative lipidoid nanoparticles internalized through a lipid raft endocytotic pathway with low cytotoxicity, strong biocompatibility and high efficacy. This study suggests that negative lipidoid nanoparticles with enema delivery constitute, uniquely and appropriately, a local anti-colorectal cancer nucleic acid drug delivery platform, and the application of similar modes may be feasible in other therapeutic settings.