title: Twist1-related miR-26b-5p suppresses epithelial-mesenchymal transition, migration and invasion by targeting SMAD1 in hepatocellular carcinoma.
abstract: Twist1 is well known to induce epithelial-mesenchymal transition (EMT) and promote tumor metastasis. MicroRNAs (miRNAs) are involved in the EMT process and are associated with metastasis in hepatocellular carcinoma (HCC). In the present study, microRNA-26b-5p (miR-26b-5p) expression was consistently and significantly downregulated in HepG2-Twist1 HCC cell lines compared with HepG2-vector cell lines using microarrays (the HepG2-Twist1 cell line can stably express Twist1). miR-26b- 5p downregulation was directly mediated by Twist1 through binding to the promoter region of miR-26b-5p in HepG2-Twist1 cells by ChIP-seq technology. Both gain- and loss-of-function studies showed that miR-26b-5p dramatically suppressed EMT and the invasion ability of HCC cells in vitro. Using mouse models, tumors derived from miR- 26b-5p-overexpressed HCC cells exhibited a significant reduction in tumorigenicity compared with the control group. Subsequent investigation revealed that miR-26b-5p directly inhibited SMAD family member 1 (SMAD1) expression. miR-26b-5p repressed BMP4/Smad1 signaling following SMAD1 inhibition. Overexpression of SMAD1 reversed the function of miR-26b-5p. In human HCC tissues and mouse xenograft tumors, miR-26b-5p levels were inversely correlated with SMAD1 expression as well as metastasis.
  
  
  CONCLUSIONS
  miR-26b-5p suppresses Twist1-induced EMT, invasion, and metastasis of HCC cells by targeting SMAD1 and BMP4/Smad1 signaling. This suggests a promising application for miR-26b-5p in anti-HCC therapy.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.|Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, China.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Prosthodontics, Affiliated Stomatological Hospital, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Dongwang
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, China.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Meili
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathology, Mudanjiang Medical University, Heilongjiang 157011, China.
authors.forename: Jindan
authors.initials: J
authors.lastname: An
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051898:Smad1 Protein / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D009687:Nuclear Proteins; D051898:Smad1 Protein; D051879:Twist-Related Protein 1; C528163:MIRN26 microRNA, human; C103173:TWIST1 protein, human
keywords: SMAD1; early recurrence; epithelial-mesenchymal transition; hepatocellular carcinoma; microRNA