title: Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma.
abstract: In gastric cancer (GC), the main subtypes (diffuse and intestinal types) differ in pathological characteristics, with diffuse GC exhibiting early disseminative and invasive behaviour. A distinctive feature of diffuse GC is loss of intercellular adhesion. Although widely attributed to mutations in the CDH1 gene encoding E-cadherin, a significant percentage of diffuse GC do not harbor CDH1 mutations. We found that the expression of the actin-modulating cytoskeletal protein, gelsolin, is significantly higher in diffuse-type compared to intestinal-type GCs, using immunohistochemical and microarray analysis. Furthermore, in GCs with wild-type CDH1, gelsolin expression correlated inversely with CDH1 gene expression. Downregulating gelsolin using siRNA in GC cells enhanced intercellular adhesion and E-cadherin expression, and reduced invasive capacity. Interestingly, hepatocyte growth factor (HGF) induced increased gelsolin expression, and gelsolin was essential for HGF-medicated cell scattering and E-cadherin transcriptional repression through Snail, Twist and Zeb2. The HGF-dependent effect on E-cadherin was found to be mediated by interactions between gelsolin and PI3K-Akt signaling. This study reveals for the first time a function of gelsolin in the HGF/cMet oncogenic pathway, which leads to E-cadherin repression and cell scattering in gastric cancer. Our study highlights gelsolin as an important pro-disseminative factor contributing to the aggressive phenotype of diffuse GC.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.
authors.forename: Baohua
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.
authors.forename: Shuo
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.|Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.|Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Ser Yue
authors.initials: SY
authors.lastname: Loo
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.
authors.forename: Arpita
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Surgery, National University Health System, Singapore.
authors.forename: Yan Lin
authors.initials: YL
authors.lastname: Yap
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore.
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.affiliation: Duke-NUS Graduate Medical School, Singapore.
authors.forename: Chia Huey
authors.initials: CH
authors.lastname: Ooi
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.
authors.forename: Thuy Duong
authors.initials: TD
authors.lastname: Dinh
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jingli
authors.initials: J
authors.lastname: Zhuo
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Lalchhandami
authors.initials: L
authors.lastname: Tochhawng
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinadhan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.
authors.forename: Tamilarasi
authors.initials: T
authors.lastname: Jegadeesan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.|Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.|Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.|Duke-NUS Graduate Medical School, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.|Department of Haematology-Oncology, National University Health System, Singapore.|National University Cancer Institute, Singapore.
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.|Department of Pathology, National University Health System, Singapore.
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.affiliation: Department of General Surgery, Singapore General Hospital, Singapore.
authors.forename: Yaw Chong
authors.initials: YC
authors.lastname: Goh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.|National University Cancer Institute, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore.|National University Cancer Institute, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley WA, Australia.|Department of Biological Sciences, University of North Texas, Denton, TX, USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: Department of Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Sutherland K
authors.initials: SK
authors.lastname: Maciver
authors.affiliation: Department of Surgery, National University Health System, Singapore.
authors.forename: Jimmy B Y
authors.initials: JB
authors.lastname: So
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore.|National University Cancer Institute, Singapore.
authors.forename: Celestial T
authors.initials: CT
authors.lastname: Yap
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D018260:Gelsolin / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018260:Gelsolin; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: E-Cadherin; cancer invasion; gastric cancer; gelsolin; hepatocyte growth factor (HGF)