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 YangAlan Prem Kumar, Sutherland K Maciver, Jimmy B Y So, Celestial T Yap

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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.

Original languageEnglish
Pages (from-to)25391-25407
Number of pages17
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - 05 Apr 2016

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    Huang, B., Deng, S., Loo, S. Y., Datta, A., Yap, Y. L., Yan, B., Ooi, C. H., Dinh, T. D., Zhuo, J., Tochhawng, L., Gopinadhan, S., Jegadeesan, T., Tan, P., Salto-Tellez, M., Yong, W. P., Soong, R., Yeoh, K. G., Goh, Y. C., Lobie, P. E., ... Yap, C. T. (2016). Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma. Oncotarget, 7(18), 25391-25407. https://doi.org/10.18632/oncotarget.8603