title: Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma.
abstract: Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelial-mesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC.
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Shigetomi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shiraha
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Nishina
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsubara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horiguchi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takaoka
authors.forename: Masaya
authors.initials: M
authors.lastname: Iwamuro
authors.forename: Junro
authors.initials: J
authors.lastname: Kataoka
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hagihara
authors.forename: Junichi
authors.initials: J
authors.lastname: Toshimori
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nouso
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D002135:Calcium-Binding Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C493729:Runx3 protein, human; C000604408:SNAI2 protein, human; D000072099:Serrate-Jagged Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin