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.

Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells

“…Gelsolin is characterized as an actin-binding protein and favors malignant progression of multiple tumor cells such as non-small lung cancer, gastric carcinoma, and glioma. 27 , 49 , 50 More importantly, several reports have indicated that Gelsolin facilitates tumor cells progression by regulating various cellular key pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK). 50 , 51 PI3K/Akt and MAPK are two classical pathways that directly regulate cell proliferation, migration, invasion, and apoptosis.…”

“… 27 , 49 , 50 More importantly, several reports have indicated that Gelsolin facilitates tumor cells progression by regulating various cellular key pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK). 50 , 51 PI3K/Akt and MAPK are two classical pathways that directly regulate cell proliferation, migration, invasion, and apoptosis. Besides, we also found SOX5 could reverse miR-195-induced downregulation of Gelsolin, indicating that Gelsolin was involved in SNHG12/miR-195-mediated promotion of glioma cell progression.…”

Does urinary peptide content differ between COPD patients with and without inherited alpha-1 antitrypsin deficiency?

“…Alterations in gelsolin expression have been associated with cigarette smoking and different pulmonary diseases such as fibrosis; however, little is known about the role of gelsolin in COPD 32–34. Gelsolin activates PI3K/Akt pathway,35 which regulates cell growth, proliferation, adhesion, migration and survival. Interestingly, it promotes the differentiation of alveolar epithelial type I and II cells from alveolar epithelial stem cells 36,37…”

Does urinary peptide content differ between COPD patients with and without inherited alpha1-antitrypsin deficiency?

“…32 Alterations in gelsolin expression have been associated with cigarette smoking and different pulmonary diseases such as fibrosis; however, little is known about the role of gelsolin in COPD. [32][33][34] Gelsolin activates PI3K/Akt pathway, 35 which regulates cell growth, proliferation, adhesion, migration and survival. Interestingly, it promotes the differentiation of alveolar epithelial type I and II cells from alveolar epithelial stem cells.…”