Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma
Data(s) |
05/04/2016
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Resumo |
<p>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.</p> |
Formato |
application/pdf |
Identificador |
http://dx.doi.org/10.18632/oncotarget.8603 http://pure.qub.ac.uk/ws/files/85103274/Gelsolin_mediated_activation_of_PI3K.pdf |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/openAccess |
Fonte |
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 , Yang , H , Kumar , A P , Maciver , S K , So , J B Y & Yap , C T 2016 , ' Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma ' Oncotarget , vol 7 , no. 18 , pp. 25391-25407 . DOI: 10.18632/oncotarget.8603 |
Tipo |
article |