Oncotarget

Research Papers:

Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma

Baohua Huang, Shuo Deng, Ser Yue Loo, Arpita Datta, Yan Lin Yap, Benedict Yan, Chia Huey Ooi, Thuy Duong Dinh, Jingli Zhuo, Lalchhandami Tochhawng, Suma Gopinadhan, Tamilarasi Jegadeesan, Patrick Tan, Manuel Salto-Tellez, Wei Peng Yong, Richie Soong, Khay Guan Yeoh, Yaw Chong Goh, Peter E. Lobie, Henry Yang, Alan Prem Kumar, Sutherland K. Maciver, Jimmy B.Y. So and Celestial T. Yap _

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Oncotarget. 2016; 7:25391-25407. https://doi.org/10.18632/oncotarget.8603

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Abstract

Baohua Huang1,*, Shuo Deng1,*, Ser Yue Loo1,2,3, Arpita Datta1, Yan Lin Yap4, Benedict Yan5, Chia Huey Ooi6, Thuy Duong Dinh1, Jingli Zhuo7, Lalchhandami Tochhawng7, Suma Gopinadhan1, Tamilarasi Jegadeesan1, Patrick Tan1,2,3,6, Manuel Salto-Tellez8, Wei Peng Yong2,9,10, Richie Soong2,11, Khay Guan Yeoh12, Yaw Chong Goh13, Peter E. Lobie2,10,14 , Henry Yang2, Alan Prem Kumar2,10,14,15,16, Sutherland K. Maciver17, Jimmy B.Y. So4 and Celestial T. Yap1,10

1 Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore

2 Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore

3 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

4 Department of Surgery, National University Health System, Singapore

5 Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore

6 Duke-NUS Graduate Medical School, Singapore

7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

8 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK

9 Department of Haematology-Oncology, National University Health System, Singapore

10 National University Cancer Institute, Singapore

11 Department of Pathology, National University Health System, Singapore

12 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

13 Department of General Surgery, Singapore General Hospital, Singapore

14 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

15 Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley WA, Australia

16 Department of Biological Sciences, University of North Texas, Denton, TX, USA

17 Department of Biomedical Sciences, University of Edinburgh, Edinburgh, UK

* These authors have contributed equally to this work as co-first authors

Correspondence to:

Celestial T. Yap, email:

Jimmy B.Y. So, email:

Keywords: gelsolin, gastric cancer, E-Cadherin, hepatocyte growth factor (HGF), cancer invasion

Received: June 29, 2015 Accepted: March 02, 2016 Published: April 05, 2016

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.


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