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

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.

Evaluation of osteoclastogenesis via NFκB decoy/mannosylated cationic liposome-mediated inhibition of pro-inflammatory cytokine production from primary cultured macrophages.

PURPOSE: To explore the effect of NFκB activation in macrophages on osteoclastogenesis of bone marrow cells for potential application as a new type of therapy for preventing bone loss. METHODS: Primary cultured macrophages and bone marrow cells were prepared from mice. As macrophage-targeted carriers, Mannosylated cationic liposomes (Man-liposomes) were prepared and were allowed to form complexes with NFκB decoy (a double-stranded oligonucleotide). Cellular uptake, inhibition of NFκB activation, and cytokine production were evaluated using macrophages. Osteoclastogenesis was investigated using bone marrow cells, which were cultured in the conditioned medium prepared from macrophages with or without Man-liposome/NFκB decoy complexes treatment. RESULTS: Cellular accumulation of NFκB decoy was enhanced by Man-liposome. NFκB activation in macrophages and TNF-α production were suppressed in macrophages by Man-liposome/NFκB decoy complexes but not by the naked NFκB decoy, Gal-liposome/NFκB decoy complexes, or Man-liposome/random decoy complexes. Osteoclastogenesis of bone marrow cells was induced in the conditioned medium prepared from activated macrophages but not by activated macrophages treated with Man-liposome/NFκB decoy complexes. CONCLUSION: Osteoclastogenesis induced by activated macrophages could be suppressed by the treatment macrophages with Man-liposome/NFκB decoy complexes. Macrophage-targeted delivery of NFκB decoys using Man-liposomes may be promising in its use for the remediation of bone loss.