RESUMO
Slit2 is often overexpressed in cancers. Slit2 is a secreted protein that binds to Roundabout (Robo) receptors to regulate cell growth and migration. Here, we employed several complementary mouse models of intestinal cancers, including the Slit2 transgenic mice, the ApcMin/+ spontaneous intestinal adenoma mouse model, and the DMH/DSS-induced colorectal carcinoma model to clarify function of Slit2/Robo1 signaling in intestinal tumorigenesis. We showed that Slit2 and Robo1 are overexpressed in intestinal tumors and may contribute to tumor generation. The Slit2/Robo1 signaling can induce precancerous lesions of the intestine and tumor progression. Ectopic expression of Slit2 activated Slit2/Robo1 signaling and promoted tumorigenesis and tumor growth. This was mediated in part through activation of the Src signaling, which then down-regulated E-cadherin, thereby activating Wnt/ß-catenin signaling. Thus, Slit2/Robo1 signaling is oncogenic in intestinal tumorigenesis.
Assuntos
Adenoma/enzimologia , Carcinoma/enzimologia , Neoplasias Colorretais/enzimologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/enzimologia , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Quinases da Família src/metabolismo , Adenoma/genética , Adenoma/patologia , Animais , Carcinoma/genética , Carcinoma/patologia , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Genes APC , Células HCT116 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Interferência de RNA , Receptores Imunológicos/genética , Transfecção , Carga Tumoral , Proteínas RoundaboutRESUMO
AIM: To investigate the anti-hepatofibrotic effects of Gardenia jasminoides in liver fibrosis. METHODS: Male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 d and were treated with Gardenia jasminoides by gavage. The effects of Gardenia jasminoides on liver fibrosis and the detailed molecular mechanisms were also assessed in human hepatic stellate cells (LX-2) in vitro. RESULTS: Treatment with Gardenia jasminoides decreased serum alanine aminotransferase (BDL vs BDL + 100 mg/kg Gardenia jasminoides, 146.6 ± 15 U/L vs 77 ± 6.5 U/L, P = 0.0007) and aspartate aminotransferase (BDL vs BDL + 100 mg/kg Gardenia jasminoides, 188 ± 35.2 U/L vs 128 ± 19 U/L, P = 0.005) as well as hydroxyproline (BDL vs BDL + 100 mg/kg Gardenia jasminoides, 438 ± 40.2 µg/g vs 228 ± 10.3 µg/g liver tissue, P = 0.004) after BDL. Furthermore, Gardenia jasminoides significantly reduced liver mRNA and/or protein expression of transforming growth factor ß1 (TGF-ß1), collagen typeâ Iâ (Colâ I) and α-smooth muscle actin (α-SMA). Gardenia jasminoides significantly suppressed the upregulation of TGF-ß1, Colâ Iâ and α-SMA in LX-2 exposed to recombinant TGF-ß1. Moreover, Gardenia jasminoides inhibited TGF-ß1-induced Smad2 phosphorylation in LX-2 cells. CONCLUSION: Gardenia jasminoides exerts antifibrotic effects in the liver fibrosis and may represent a novel antifibrotic agent.