RESUMO
MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.
Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , MicroRNAs/metabolismo , Neoplasias Experimentais/genética , Animais , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Suplementos Nutricionais , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/prevenção & controle , Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , NF-kappa B/metabolismo , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Nitrosaminas/toxicidade , Ratos , Ratos Transgênicos , Transdução de Sinais/genética , Zinco/administração & dosagem , Zinco/deficiênciaRESUMO
Effective animal models are needed to evaluate the feasibility of new techniques to assess portal hypertension (PH). Here we developed 2 canine models of acute PH by increasing intrasinusoidal resistance and by increasing the portal vein (PV) flow volume to test the efficacy of a noninvasive technique to evaluate PH. The acute low-flow PH model was based on embolization of liver circulation by using a gelatin sponge material. The acute high-flow PH model was based on increasing the PV flow volume by using an arteriovenous (A-V) shunt from the femoral artery and saline infusion. PV pressures and diameters were assessed before and after inducing PH. Pressure values and diameters were obtained from the inferior vena cava in 3 unmanipulated controls. The low-flow model of PH was repeatable and successfully increased PV pressure by an average of 16.5 mm Hg within 15 min. The high-flow model of PH failed to achieve increased PV pressures. However, saline supplementation of the portal circulation in the high-flow model led to mean increases in PV pressures of 12.8 mm Hg within 20 min. Pulsatility in the PV was decreased in the low-flow model and increased in the high-flow model relative to baseline. No changes in PV diameter were noted in either model. These acute PH models are relatively straightforward to implement and may facilitate the evaluation of new techniques to assess PH.
