RESUMO
Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD3) is a crucial oncogene in human lung cancer, whereas protein kinase C δ (PKCδ) acts as a tumor suppressor. In this study, we aimed to explore the regulation by PLOD3 on the expression of YAP1 to affect the progression of non-small cell lung cancer (NSCLC) via the PKCδ/CDK1/LIMD1 signaling pathway. We found that PLOD3, CDK1, and YAP1 were highly expressed, while LIMD1 was poorly expressed in NSCLC tissues. Mechanistic investigation demonstrated that silencing PLOD3 promoted the cleavage of PKCδ in a caspase-dependent manner to generate a catalytically active fragment cleaved PKCδ, enhanced phosphorylation levels of CDK1, and LIMD1 but suppressed nuclear translocation of YAP1. Furthermore, functional experimental results suggested that loss of PLOD3 led to increased phosphorylation levels of CDK1 and LIMD1 and downregulated YAP1, thereby suppressing the proliferation, colony formation, cell cycle entry, and resistance to apoptosis of NSCLC cells in vitro and inhibiting tumor growth in vivo. Taken together, these results show that PLOD3 silencing activates the PKCδ/CDK1/LIMD1 signaling pathway to prevent the progression of NSCLC, thus providing novel insight into molecular targets for treating NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Apoptose , Proteína Quinase CDC2/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Proteínas de Sinalização YAPRESUMO
AIM: To investigate the potential role of microRNA-30a (miR-30a) in esophageal squamous cell carcinoma (ESCC). METHODS: Expression of miR-30a-3p/5p was analyzed using microarray data and fresh ESCC tissue samples. Both in vitro and in vivo assays were used to investigate the effects of miR-30a-3p/5p on ESCC cell proliferation. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis was performed to explore underlying mechanisms involved in ESCC, and then, assays were carried out to verify the potential molecular mechanism of miR-30a in ESCC. RESULTS: Low expression of miR-30a-3p/5p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC. Knock-down of miR-30a-3p/5p promoted ESCC cell proliferation. Increased miR-30a-3p/5p expression inhibited the Wnt signaling pathway by targeting Wnt2 and Fzd2. CONCLUSION: Down-regulation of miR-30a-3p/5p promotes ESCC cell proliferation by activating the Wnt signaling pathway through inhibition of Wnt2 and Fzd2.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Receptores Frizzled/genética , MicroRNAs/metabolismo , Via de Sinalização Wnt/genética , Proteína Wnt2/genética , Regiões 3' não Traduzidas/genética , Animais , Biópsia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Linhagem Celular Tumoral , Proliferação de Células/genética , Conjuntos de Dados como Assunto , Progressão da Doença , Regulação para Baixo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago , Esôfago/cirurgia , Receptores Frizzled/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Análise em Microsséries , Prognóstico , Proteína Wnt2/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The classical inflammatory biomarker, C-reactive protein (CRP), has been identified to be related to progression of esophageal cancer. Some research showed that elevated pretreatment serum CRP indicated a poor prognosis, but results have been inconsistent. MATERIALS AND METHODS: We searched the Medline, Embase and the Cochrane Central Search Library for suitable studies and a meta-analysis of eleven (1,886 patients) was conducted to examine the relationship between elevated serum CRP level and overall survival (OS) in esophageal cancer cases. Moreover, correlation analyses were conducted to assess links between pretreatment serum CRP level and tumor node metastasis (TNM) stage as well as T, N, M grade, respectively. RESULTS: The pooled analysis showed that elevated pretreatment serum CRP level was significantly associated with poorer overall survival (HR 2.09, 95%CI 1.52-2.87, p<0.01). Subgroup analyses were conducted by "country", "cut-off value", "treatment" and "number of patients", and no single factor could alter the result. Elevated pretreatment serum CRP was significantly correlated with more advanced TNM stage and T, N, M grade respectively. CONCLUSIONS: Elevated pretreatment serum CRP levels are associated with poorer prognosis in esophageal cancer patients, and could serve as a useful biomarker for outcome prediction.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Estudos de Casos e Controles , Progressão da Doença , Humanos , PrognósticoRESUMO
BACKGROUND: Several animal models have been established to investigate the mechanisms of obliterative bronchiolitis after lung transplantation. In this study, we compared three prevalent murine models of obliterative bronchiolitis in terms of several basic pathologic changes in a relatively short span of time after transplantation. METHODS: Each of the recipient mice simultaneously received orthotopic, intra-omental and subcutaneous tracheal transplantation in both syngeneic and allogeneic settings. No immunosuppressive treatment was administered. Tracheal grafts were harvested on Day 14, 21 and 28 after transplantation for histological and immunohistochemical analyses. RESULTS: Syngeneic tracheal grafts from different transplant sites retained normal histologic structures, while their corresponding allografts demonstrated more occlusion of the airway lumen as well as more infiltration of CD4(+)/CD8(+) mononuclear cells and myofibroblasts, but less regenerative epithelium and neovascularized vessels at indicated times (P<0.05). Compared with two heterotopic allografts, orthotopic allografts had less occlusion of the tracheal lumen as well as less infiltration of CD4(+)/CD8(+) mononuclear cells and myofibroblasts, but more regenerative epithelium and neovascularized vessels (P<0.05). CONCLUSIONS: Orthotopic tracheal transplantation in mice can be considered as a model to study early stages of obliterative bronchiolitis, and heterotopic tracheal transplantation can be a model for late stages of obliterative bronchiolitis.
Assuntos
Bronquiolite Obliterante/patologia , Traqueia/patologia , Traqueia/transplante , Animais , Bronquiolite Obliterante/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Transplante de Pulmão/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Neovascularização Fisiológica/imunologia , Transplante Heterotópico/efeitos adversos , Transplante Homólogo/efeitos adversosRESUMO
OBJECTIVE: To determine the protective mechanism of preconditioning to the lung injury induced by ischemia-reperfusion. METHODS: Twelve pigs were randomly divided into 2 groups: control group ( Group C) and ischemic preconditioning group ( Group IP). The concentration of superoxide distrautase (SOD) and malondialdehyde (MDA) in circuit were checked before and after the perfusion to reflect the lipid peroxidation in the lungs. Left lung biopsies were performed immediately after the perfusion and 1 hour postperfusion for histologic examination. The ICAM-1 expression was assessed by immunohistochemical analysis with Envision method and the mRNA expression of ICAM-1 was analyzed by RT-PCR. RESULTS: SOD in Group IP was much higher than that in Group C (P < 0.01 ). MDA in Group IP was much lower than that in Group C ( P < 0.01 ). The lung histologic examination showed that Group C was significantly more serious than Group IP in pulmonary edema, inflammatory cell infiltration, mild focal hemorrhage, and alveolar disruption. The expression of ICAM-1 of lung tissue obviously decreased in Group IP than that in Group C (P <0.01 ). The expression of ICAM-1 mRNA of lung tissue was significantly lower in Group IP than that in Group C (P < 0.01 ). CONCLUSION: Lung ischemic preconditioning can reduce the lung injury. The mechanisms of the protective effects of the IP may be related to the increase of SOD and the decrease of MDA. The preconditioning down-regulated the ICAM-1 expression is one of the mechanisms in reducing the lung injury.