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Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression.

Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, Jiang H, Ren J, Cai J, Li Q - BMC Cancer (2015)

Bottom Line: We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo.Inhibition effect of resveratrol on TGF-β-induced EMT was examined by morphological observation.Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-β1-induced EMT.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ttt99118@hotmail.com.

ABSTRACT

Background: Resveratrol extracted from grape has been an ideal alternative drug in the therapy of different cancers including colorectal cancer (CRC). Since the underlying mechanisms of resveratrol on the invasion and metastasis of CRC have not been fully elucidated, and epithelial-to-mesenchymal transition (EMT) is a key process associated with the progression of CRC, here we aimed to investigate the potential mechanism of resveratrol on the inhibition of TGF-β1-induced EMT in CRC LoVo cells.

Methods: We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo. In vivo, the impact of resveratrol on invasion and metastasis was investigated by mice tail vein injection model and mice orthotopic transplantation tumor model. In vivo imaging was applied to observe the lungs metastases, and hemaoxylin-eosin (HE) staining was used to evaluate metastatic lesions. In vitro, impact of resveratrol on the migration and invasion of LoVo cells was evaluated by transwell assay. Inhibition effect of resveratrol on TGF-β-induced EMT was examined by morphological observation. Epithelial phenotype marker E-cadherin and mesenchymal phenotype marker Vimentin were detected by western blot and immunofluorescence. Promoter activity of E-cadherin was measured using a dual-luciferase assay kit. mRNA expression of Snail and E-cadherin was measured by RT-PCR.

Results: We demonstrated that, resveratrol inhibited the lung metastases of LoVo cells in vivo. In addition, resveratrol reduced the rate of lung metastases and hepatic metastases in mice orthotopic transplantation. In vitro, TGF-β1-induced EMT promoted the invasion and metastasis of CRC, reduced the E-cadherin expression and elevated the Vimentin expression, and activated the TGF-β1/Smads signaling pathway. But resveratrol could inhibit the invasive and migratory ability of LoVo cells in a concentration-dependent manner, increase the expression of E-cadherin, repress the expression of Vimentin, as well as the inhibition of TGF-β1/Smads signaling pathway. Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-β1-induced EMT.

Conclusions: Our new findings provided evidence that, resveratrol could inhibit EMT in CRC through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in CRC.

No MeSH data available.


Related in: MedlinePlus

Resveratrol inhibited the metastasis of colorectal cancer LoVo cells in vitro and in vivo imaging by tail vein injection. (A) Correlation of resveratrol drug concnetrations (0, 6.25, 12.5, 25, 50, 100, 200 μM) and cell viability in LoVo cells for 48 h and 72 h. (B) LoVo-pLV4-GFP cells were respectively injected into the lateral tail vein. One week later, resveratrol was administrated with the concentration of 0, 50 mg/Kg, 100 mg/Kg, 150 mg/Kg every day for 3 weeks. Seven weeks later, the established lungs metastases images were observed by LB983 NIGHTOWL II system. (C) The organs of lung were excised, and the metastasis was checked by hemaoxylin-eosin staining, and the numbers of metastatic lesions were counted. **P < 0.01, compared with LoVo-pLV4-GFP cells without treatment of resveratrol.
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Fig1: Resveratrol inhibited the metastasis of colorectal cancer LoVo cells in vitro and in vivo imaging by tail vein injection. (A) Correlation of resveratrol drug concnetrations (0, 6.25, 12.5, 25, 50, 100, 200 μM) and cell viability in LoVo cells for 48 h and 72 h. (B) LoVo-pLV4-GFP cells were respectively injected into the lateral tail vein. One week later, resveratrol was administrated with the concentration of 0, 50 mg/Kg, 100 mg/Kg, 150 mg/Kg every day for 3 weeks. Seven weeks later, the established lungs metastases images were observed by LB983 NIGHTOWL II system. (C) The organs of lung were excised, and the metastasis was checked by hemaoxylin-eosin staining, and the numbers of metastatic lesions were counted. **P < 0.01, compared with LoVo-pLV4-GFP cells without treatment of resveratrol.

Mentions: First, we determined the cytotoxic effect of resveratrol on colorectal cancer LoVo cells using CCK assay. As shown in Figure 1A, LoVo cells were treated with various concentrations of resveratrol (0, 6.25, 12.5, 25, 50, 100, 200 μM) for 48 h and 72 h. It was observed that, resveratrol inhibited the proliferation of LoVo cells in a concentration- and time-dependent manner. After 48 h of resveratrol (12.5 μM) treatment, cell viability was reduced by approximately 10%, and this data indicated that less than 12.5 μM resveratrol had little influence on the cell proliferation of LoVo cells, while more than 50 μM resveratrol significantly inhibited the proliferation of LoVo cells (P < 0.01).Figure 1


Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression.

Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, Jiang H, Ren J, Cai J, Li Q - BMC Cancer (2015)

Resveratrol inhibited the metastasis of colorectal cancer LoVo cells in vitro and in vivo imaging by tail vein injection. (A) Correlation of resveratrol drug concnetrations (0, 6.25, 12.5, 25, 50, 100, 200 μM) and cell viability in LoVo cells for 48 h and 72 h. (B) LoVo-pLV4-GFP cells were respectively injected into the lateral tail vein. One week later, resveratrol was administrated with the concentration of 0, 50 mg/Kg, 100 mg/Kg, 150 mg/Kg every day for 3 weeks. Seven weeks later, the established lungs metastases images were observed by LB983 NIGHTOWL II system. (C) The organs of lung were excised, and the metastasis was checked by hemaoxylin-eosin staining, and the numbers of metastatic lesions were counted. **P < 0.01, compared with LoVo-pLV4-GFP cells without treatment of resveratrol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362662&req=5

Fig1: Resveratrol inhibited the metastasis of colorectal cancer LoVo cells in vitro and in vivo imaging by tail vein injection. (A) Correlation of resveratrol drug concnetrations (0, 6.25, 12.5, 25, 50, 100, 200 μM) and cell viability in LoVo cells for 48 h and 72 h. (B) LoVo-pLV4-GFP cells were respectively injected into the lateral tail vein. One week later, resveratrol was administrated with the concentration of 0, 50 mg/Kg, 100 mg/Kg, 150 mg/Kg every day for 3 weeks. Seven weeks later, the established lungs metastases images were observed by LB983 NIGHTOWL II system. (C) The organs of lung were excised, and the metastasis was checked by hemaoxylin-eosin staining, and the numbers of metastatic lesions were counted. **P < 0.01, compared with LoVo-pLV4-GFP cells without treatment of resveratrol.
Mentions: First, we determined the cytotoxic effect of resveratrol on colorectal cancer LoVo cells using CCK assay. As shown in Figure 1A, LoVo cells were treated with various concentrations of resveratrol (0, 6.25, 12.5, 25, 50, 100, 200 μM) for 48 h and 72 h. It was observed that, resveratrol inhibited the proliferation of LoVo cells in a concentration- and time-dependent manner. After 48 h of resveratrol (12.5 μM) treatment, cell viability was reduced by approximately 10%, and this data indicated that less than 12.5 μM resveratrol had little influence on the cell proliferation of LoVo cells, while more than 50 μM resveratrol significantly inhibited the proliferation of LoVo cells (P < 0.01).Figure 1

Bottom Line: We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo.Inhibition effect of resveratrol on TGF-β-induced EMT was examined by morphological observation.Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-β1-induced EMT.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ttt99118@hotmail.com.

ABSTRACT

Background: Resveratrol extracted from grape has been an ideal alternative drug in the therapy of different cancers including colorectal cancer (CRC). Since the underlying mechanisms of resveratrol on the invasion and metastasis of CRC have not been fully elucidated, and epithelial-to-mesenchymal transition (EMT) is a key process associated with the progression of CRC, here we aimed to investigate the potential mechanism of resveratrol on the inhibition of TGF-β1-induced EMT in CRC LoVo cells.

Methods: We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo. In vivo, the impact of resveratrol on invasion and metastasis was investigated by mice tail vein injection model and mice orthotopic transplantation tumor model. In vivo imaging was applied to observe the lungs metastases, and hemaoxylin-eosin (HE) staining was used to evaluate metastatic lesions. In vitro, impact of resveratrol on the migration and invasion of LoVo cells was evaluated by transwell assay. Inhibition effect of resveratrol on TGF-β-induced EMT was examined by morphological observation. Epithelial phenotype marker E-cadherin and mesenchymal phenotype marker Vimentin were detected by western blot and immunofluorescence. Promoter activity of E-cadherin was measured using a dual-luciferase assay kit. mRNA expression of Snail and E-cadherin was measured by RT-PCR.

Results: We demonstrated that, resveratrol inhibited the lung metastases of LoVo cells in vivo. In addition, resveratrol reduced the rate of lung metastases and hepatic metastases in mice orthotopic transplantation. In vitro, TGF-β1-induced EMT promoted the invasion and metastasis of CRC, reduced the E-cadherin expression and elevated the Vimentin expression, and activated the TGF-β1/Smads signaling pathway. But resveratrol could inhibit the invasive and migratory ability of LoVo cells in a concentration-dependent manner, increase the expression of E-cadherin, repress the expression of Vimentin, as well as the inhibition of TGF-β1/Smads signaling pathway. Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-β1-induced EMT.

Conclusions: Our new findings provided evidence that, resveratrol could inhibit EMT in CRC through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in CRC.

No MeSH data available.


Related in: MedlinePlus