Dataset Information

JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-?/Smad Mediated Snail/E-Cadherin Expression.

ABSTRACT: JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-?-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-?-stimulated CRC cells in a concentration-dependent manner through increasing the expression of E-cadherin and repressing the expression of Vimentin, as well as the inhibition of TGF-?/Smad signaling pathway. Meanwhile, JPJD reduced the transcriptional activities of EMT-associated factors Snail and E-cadherin during the initiation of TGF-?-induced EMT. In vivo, the results demonstrated that JPJD can significantly inhibit the liver and lung metastasis of orthotopic CRC tumor in nude mice, as well as significantly prolonging the survival time of tumor-bearing in a dose-dependent manner. Additionally, JPJD can upregulate the expression of E-cadherin and Smad2/3 in the cytoplasm and downregulate the expression of Vimentin, p-Smad2/3, and Snail in the orthotopic CRC tumor tissues. In conclusions, our new findings provided evidence that JPJD could inhibit TGF-?-induced EMT in CRC through TGF-?/Smad mediated Snail/E-cadherin expression.

SUBMITTER: Liu X

PROVIDER: S-EPMC5337333 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-β/Smad Mediated Snail/E-Cadherin Expression.

Liu Xuan X Ji Qing Q Deng Wanli W Chai Ni N Feng Yuanyuan Y Zhou Lihong L Sui Hua H Li Chunpu C Sun Xiaoting X Li Qi Q

BioMed research international 20170216

JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-β-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-β-stimulated CRC cells in a concentration-dependent ma ...[more]

PMID: 28299321

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Project description:AimPaeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-? mediated pulmonary EMT in bleomycin-induced PF mice.MethodsPF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg). The mice were orally treated with paeoniflorin or prednisone for 21 d. After the mice were sacrificed, lung tissues were collected for analysis. An in vitro EMT model was established in alveolar epithelial cells (A549 cells) incubated with TGF-?1 (2 ng/mL). EMT identification and the expression of related proteins were performed using immunohistochemistry, transwell assay, ELISA, Western blot and RT-qPCR.ResultsIn PF mice, paeoniflorin (50, 100 mg·kg(-1)·d(-1)) or prednisone (6 mg·kg(-1)·d(-1)) significantly decreased the expression of FSP-1 and ?-SMA, and increased the expression of E-cadherin in lung tissues. In A549 cells, TGF-?1 stimulation induced EMT, as shown by the changes in cell morphology, the increased cell migration, and the increased vimentin and ?-SMA expression as well as type I and type III collagen levels, and by the decreased E-cadherin expression. In contrast, effects of paeoniflorin on EMT disappeared when the A549 cells were pretreated with TGF-?1 for 24 h. TGF-?1 stimulation markedly increased the expression of Snail and activated Smad2/3, Akt, ERK, JNK and p38 MAPK in A549 cells. Co-incubation with paeoniflorin (1-30 ?mol/L) dose-dependently attenuated TGF-?1-induced expression of Snail and activation of Smad2/3, but slightly affected TGF-?1-induced activation of Akt, ERK, JNK and p38 MAPK. Moreover, paeoniflorin markedly increased Smad7 level, and decreased ALK5 level in A549 cells.ConclusionPaeoniflorin suppresses the early stages of TGF-? mediated EMT in alveolar epithelial cells, likely by decreasing the expression of the transcription factors Snail via a Smad-dependent pathway involving the up-regulation of Smad7.

Project description:An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFβ signaling. This was also supported by the presence and release of higher concentration of endogenous TGFβ1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFβ1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFβ1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFβ-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development.

Dataset Information

JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-?/Smad Mediated Snail/E-Cadherin Expression.

Publications

JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-<i>β</i>/Smad Mediated Snail/E-Cadherin Expression.

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