Girdin interaction with vimentin induces EMT and promotes the growth and metastasis of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer of the digestive tract that has a high potential for metastasis and a poor prognosis. Girdin was first reported in 2005 as an actin-binding protein and was designated as Akt-phosphorylation enhancer (APE); thus, Girdin has been revealed to have an important role in regulating cancer development. There is additional evidence indicating that Girdin is associated with cell proliferation, migration, invasion and survival in certain cancers. However, the potential mechanisms involving Girdin and mobility in pancreatic cancer have not been elucidated. In the present study, it was revealed that Girdin was highly expressed in pancreatic cancer tissue and was associated with tumor grade. The present study, to the best of our knowledge, is the first aimed at investigating the unknown role of Girdin in PDAC metastasis. A short hairpin RNA for Girdin (sh-Girdin) was successfully constructed with recombinant adenoviral vectors to suppress the expression of Girdin in pancreatic cancer cell lines (PANC-1 and BXPC-3). The silencing efficiency of the Girdin shRNA was determined by RT-qPCR and western blot analysis, and decreased Girdin expression in the cytoplasm was revealed by immunofluorescence detection. Then, sulforhodamine B (SRB) and colony formation assays were used to confirm that the knockdown of Girdin inhibited proliferation in vitro, and Transwell assays were used to examine the influence of Girdin knockdown on cellular mobility. Animal experiments also confirmed that silencing the expression of Girdin in pancreatic cancer cells inhibited the growth and metastasis of pancreatic cancer in vivo. Transforming growth factor-β (TGF-β) is a common inducer of epithelial-mesenchymal transition (EMT) and can effectively induce EMT in PDAC. Notably, TGF-β-treated cells exhibited changes in the classic biological markers of EMT. The expression of E-cadherin, a marker of the epithelial phenotype, increased, and the expression of N-cadherin and vimentin, markers of the interstitial phenotype, decreased in response to sh-Girdin. According to these experiments, Girdin may affect pancreatic cancer progression and development by interacting with vimentin. Therefore, there is evidence indicating that Girdin could be designated as a prognostic biological indicator and a candidate therapeutic target for pancreatic cancer.

FBLN5 is targeted by microRNA‑27a‑3p and suppresses tumorigenesis and progression in high‑grade serous ovarian carcinoma

“…Tu et al (13) and Lee et al (35), reported that FBLN5 was involved in EMT and affected the invasion and migration by tumor-associated MMPs in breast cancer and hepatocellular carcinoma cells. EMT is a cellular process and is often defined as the loss of epithelial characteristics and the increase in mesenchymal features (36,37). Consistent with this hypothesis, the results in the present study revealed that FBLN5 overexpression increased the epithelial marker, E-cadherin and decreased the mesenchymal markers, N-cadherin and Snail.…”

Mechanical and Non‐Mechanical Functions of Filamentous and Non‐Filamentous Vimentin

“…[ 18 ] Another actin regulatory protein, girdin, that links protein kinase B (AKT) signaling to cytoskeletal dynamics was shown to bind vimentin by mass spectrometry and immunoprecipitation from pancreatic cancer cells. [ 19 ] Hic‐5, a focal adhesion scaffold protein stabilizes the VIF network by modulation of RhoGTPases, and its ablation leads to the disassembly of VIF. [ 20 ] Filamin A, an actin crosslinker, directs the kinase PAK1 to vimentin, altering its assembly into VIFs.…”

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

“…These results suggest that the proproliferation and anti-apoptotic functions of KLK8 may not be dependent on activation of Notch signaling pathway. Notably, our GSEA analysis data showed that KLK8 overexpression might also lead to the activation of EMT (epithelial-mesenchymal transition), glycolysis and KRAS signaling pathway, which have been implicated in the pathogenesis and progression of pancreatic cancers [17,[43][44][45]. Whether these processes and the related signaling pathways contribute to the KLK8-induced pro-proliferation and anti-apoptotic effects in pancreatic cancers merits further investigation.…”