RESUMO
Abnormal translation of the MYC proto-oncogene is a hallmark of the initiation and maintenance of tumorigenesis. However, the molecular mechanism underlying increased MYC protein levels in certain cancer types without a corresponding increase in MYC mRNA levels is unclear. Here, we identified a novel lncRNA, MTAR1, which is critical for post-transcriptional regulation of MYC-induced tumorigenesis. MTAR1 is essential for recruiting IGF2BPs into PABP1-mediated liquid-liquid phase separation (LLPS) complexes and facilitates IGF2BPs-mediated MYC mRNA translation. MTAR1 enhanced binding between IGF2BPs and PABP1, thereby promoting MYC mRNA stability and increased MYC mRNA translation. In summary, MTAR1 is a novel MYC-related lncRNA that contributes to tumor progression by enhancing MYC translation through mediating PABP1/IGF2BPs liquid-liquid phase separation.
Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-myc , RNA Longo não Codificante , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
Multiple myeloma (MM), a hematological malignancy, has a poor prognosis and requires an invasive procedure. Reports have implicated miRNAs in the diagnosis, treatment and prognosis of hematological malignancies. In our study, we evaluated the expression profiles of miR-17-3p in plasma and bone marrow mononuclear cells of monoclonal gammopathy of undetermined significance (MGUS) and MM patients and healthy subjects. The results showed that the plasma and mononuclear cell expression levels of miR-17-3p in MM patients were higher than those in MGUS patients and normal controls. In addition, the expression of miR-17-3p was positively correlated with diagnostic indexes, such as marrow plasma cell abundance and serum M protein level, and positively correlated with the International Staging System stage of the disease. Receiver operating characteristic curve analysis suggested that miR-17-3p might be a diagnostic index of MM. Moreover, miR-17-3p regulated cell proliferation, apoptosis and the cell cycle through P21 in MM cell lines and promoted MM tumor growth in vivo. Furthermore, we predicted and verified LMLN as a functional downstream target gene of miR-17-3p. Negatively regulated by miR-17-3p, LMLN inhibits MM cell growth, exerting a tumor suppressive function through P21. Taken together, our data identify miR-17-3p as a promising diagnostic biomarker for MM in the clinic and unveil a new miR-17-3p-LMLN-P21 axis in MM progression.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Metaloendopeptidases/genética , MicroRNAs/genética , Mieloma Múltiplo/patologia , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloendopeptidases/metabolismo , Camundongos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Transplante de NeoplasiasRESUMO
Hyperthermia cancer treatment is an adjunctive therapy that aims at killing the tumor cells with excessive heat that is usually generated by metal contrasts exposed to alternating magnetic field. The efficacy of hyperthermia is often limited by the heat damage to normal tissue due to indiscriminate distribution of the metal contrasts within the body. Tumor-targeting metal contrasts may reduce the toxicity of hyperthermia and improve the efficacy of thermotherapy against cancer. MUC1 is a glycoprotein over expressed in most adenocarcinomas, and represents an attractive therapeutic target. In this study, a MUC1 aptamer is conjugated with iron nanoparticles to construct adenocarcinoma-targeting metal contrasts. DNA hybridization studies confirmed that the aptamers were conjugated to the iron nanoparticles. Importantly, more aptamer-modified nanoparticles attached to the MUC1-positive cancer cells compared with the unmodified nanoparticles. Moreover, aptamer-modified nanoparticles significantly enhanced the targeted hyperthermia damage to MUC1-positive cancer cells in vitro (p < 0.05). The results suggest that MUC1 aptamer-modified metal particles may have potential in development of targeted hyperthermia therapy against adenocarcinomas.
Assuntos
Adenocarcinoma/patologia , Aptâmeros de Nucleotídeos/química , Febre/patologia , Ferro/química , Nanopartículas Metálicas , Mucina-1/química , Linhagem Celular Tumoral , Humanos , MagnetismoRESUMO
Multidrug resistance (MDR) is a major impediment to cancer treatment. A promising strategy for treating MDR is the joint delivery of combined anticancer agents to tumor cells in a single nanocarrier. Here, for the first time, Resveratrol (Res) was co-encapsulated with paclitaxel (PTX) in a PEGylated liposome to construct a carrier-delivered form of combination therapy for drug-resistant tumors. The composite liposome had an average diameter of 50 nm with encapsulated efficiencies of above 50%. The studies demonstrated that the composite liposome could generate potent cytotoxicity against the drug-resistant MCF-7/Adr tumor cells in vitro and enhance the bioavailability and the tumor-retention of the drugs in vivo. Moreover, systemic therapy with the composite liposome effectively inhibited drug-resistant tumor in mice (p < 0.01), without any notable increase in the toxicity. These results suggested that the co-delivery of Res and a cytotoxic agent in a nanocarrier may potentially improve the treatment of drug-resistant tumors.
