title: Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/β-catenin signaling pathway.
abstract: The canonical Wnt/β-catenin signaling pathway has been shown to promote the epithelial-mesenchymal transition (EMT), which is a crucial process in multiple embryonic developmental processes and the progression of carcinomas. We recently provided evidence that leucine-rich repeat flightless-1-interacting protein 1 (LRRFIP1) promotes cancer metastasis and invasion. In the present study, we identified the signaling elements targeted by LRRFIP1 for promotion of the EMT in pancreatic and lung cancer. LRRFIP1 silencing reversed the EMT, as shown by increased expression of E-cadherin (an epithelial marker) and decreased expression of vimentin (a mesenchymal marker). Silencing of LRRFIP1 up-regulated phosphorylation of β-catenin and decreased its nuclear localization by targeting the β-catenin destruction complex. The expression of β-catenin and E-cadherin in the plasma membrane fraction was increased in LRRFIP1 silenced cancer cells, and the migration and invasion capabilities were strongly inhibited. In addition, this protein was highly expressed at the invasion front of malignant tissue collected from pancreatic cancer patients. Consequently, our data strongly suggested that LRRFIP1 played an important role in the invasion of carcinoma cells. Our data provide experimental evidence that LRRFIP1 is an attractive candidate for targeted therapy in human cancers.
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Douchi
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. Electronic address: ohtsuka@surg1.med.tohoku.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Ohtsuka
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Ariake
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kawasaki
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukase
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Oikawa
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naitoh
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; Division of Integrated Surgery and Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Katayose
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Egawa
authors.affiliation: Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; Division of Integrated Surgery and Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
mesh_terms: D021581:Active Transport, Cell Nucleus; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; C114370:LRRFIP1 protein, human; D016601:RNA-Binding Proteins; D051176:beta Catenin
keywords: EMT; LRRFIP1; Reverse EMT; Wnt/β-catenin signaling; β-catenin destruction complex