RESUMO
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.
Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Fosfoproteínas/metabolismo , Proteólise , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Quinase do Linfoma Anaplásico , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Nus , Metástase Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteínas de Ligação a RNA/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , NucleolinaRESUMO
The role of specificity protein 1 (Sp1) in controlling gene expression in lung tumor development and metastasis is not well understood. In this study, we showed that the Sp1 level was highly increased and required for lung tumor growth in transgenic mice bearing Kras-induced lung tumors under the control of doxycycline. Furthermore, the Sp1 level was highly upregulated in lung adenocarcinoma cells with low invasiveness and in patients with stage I lung cancer. We also demonstrated that Sp1 was downregulated in lung adenocarcinoma cells with high invasiveness and in patients with stage IV lung adenocarcinoma. Moreover, Sp1 inversely regulated migration, invasion and metastasis of lung adenocarcinoma cells in vivo. In addition, a decrease in the Sp1 level in highly invasive lung adenocarcinoma cells resulted from instability of the Sp1 protein. Furthermore, overexpression of Sp1 in highly invasive lung adenocarcinoma cells increased expression of E-cadherin, a suppressor of metastasis, and attenuated the translocation of ß-catenin into the cellular nucleus that leads to tumor malignancy. Taken together, Sp1 level accumulated strongly in early stage and then declined in late stage, which is important for lung cancer cell proliferation and metastasis during tumorigenesis.
Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Fator de Transcrição Sp1/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Caderinas/biossíntese , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Fator de Transcrição Sp1/genética , beta Catenina/metabolismoRESUMO
A series of 1-(4-biphenylyl)pentyl hydrogen 3-alkylglutarates and 3-hydroxy-3-alkylglutarates was synthesized and assayed for inhibition of rat liver beta-hydroxy-beta-methylglutaryl-CoA reductase. Limited solubility of the monoesters in the enzyme assay system prevented the determination of the I50 values. However, the limited data indicated no significant changes in the activity of the analogs when they were assayed at identical concentrations.