title: Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression.
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.
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ttt99118@hotmail.com.|Research Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ttt99118@hotmail.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. lxtw@hotmail.com.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. zhifenghan1984@163.com.
authors.forename: Zhifen
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. zlhtcm@hotmail.com.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. lqsh_2007@126.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Sui
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. linlinyan2014@163.com.
authors.forename: Linlin
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. hailijiang2014@126.com.
authors.forename: Haili
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Shanghai Municipal Hospital of Traditional Chinese Medicine, Department of Oncology, Shanghai, 200071, China. jianlinren2014@163.com.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, FL, 33620, USA. jianfeng_cai67@163.com.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Lzwf@hotmail.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D015820:Cadherins; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D013267:Stilbenes; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000077185:Resveratrol