GPX2 silencing relieves epithelial–mesenchymal transition, invasion, and metastasis in pancreatic cancer by downregulating Wnt pathway

Abstract

Glutathione peroxidase 2 (GPX2) participates in many cancers including pancreatic cancer (PC), and overexpression of GPX2 promotes tumor growth. Herein, we identified the role of GPX2 in epithelial–mesenchymal transformation (EMT), invasion, and metastasis in PC. Bioinformatics prediction was applied to select PC‐related genes. The regulatory function of GPX2 in PC was explored by treatment with short hairpin RNA against GPX2 or LiCl (activator of wingless‐type MMTV integration site [Wnt] pathway) in PC cells. GPX2 level in PC tissues, the levels of GPX2, β‐catenin, Vimentin, Snail, epithelial‐cadherin (E‐cadherin), matrix metalloproteinase 2 (MMP2), MMP9, and Wnt2 in cells were determined. Subsequently, cell proliferation, invasion, and metastasis were assayed. Bioinformatics analysis revealed that GPX2 was involved in PC development mediated by the Wnt pathway. GPX2 was highly expressed in PC tissues. GPX2 silencing downregulated levels of β‐catenin, Vimentin, Snail, MMP2, MMP9, and Wnt2 but upregulated levels of E‐cadherin. It was confirmed that GPX2 silencing suppressed PC cell proliferation, metastasis, and invasion. Furthermore, the trend of EMT and invasion and metastasis of PC induced by the LiCl‐activated Wnt pathway was reversed when the GPX2 was silenced. GPX2 silencing could inhibit the Wnt pathway, subsequently suppress PC development.

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…Interestingly, and in accordance t our ndings, reduced expression of GPX3 has been shown to be linked to increased proliferation rate in NSCLC by modulating redox mediated signals [105]. Further, GPX2 is associated with invasion, metastasis and tumor growth, as GPX2 knock down reduced levels of EMT markers such as vimentin, SNAI1 and MMP2 [106].…”

Analysis of Epithelial-Mesenchymal Transition Metabolism Identifies Possible Cancer Biomarkers Useful in Diverse Genetic Backgrounds

“…Several studies have described that GPX genes are critical for EMT, either preventing or enhancing it ( 23 – 25 ). Specifically, GPX2 downregulation is contrasting because it has been reported as a regulator of EMT markers, enhancing invasion, and metastasis targeting the Wnt pathway in cervical and pancreatic cancer ( 26 , 30 ). Nevertheless, NSCLC cells usually have an aberrant Wnt pathway, explaining why this could be different in these cells ( 31 ).…”

“…At the transcriptional level, EMT downregulated the expression of GPX2 and GSR in A549, HCC827, and NCI-H358 cell lines. Furthermore, GSR and GPX genes have already been reported as essential features to block EMT in melanoma cells, cervical cancer, hepatocellular carcinoma, gastric, pancreatic, breast, and colon cancers ( 23 – 26 , 30 , 42 , 43 ). Hence, these findings supply evidence that the downregulation of GPX2 and GSR may be necessary for EMT induction on NSCLC cell lines.…”

<p>Enhanced and Prolonged Antitumor Effect of Salinomycin-Loaded Gelatinase-Responsive Nanoparticles via Targeted Drug Delivery and Inhibition of Cervical Cancer Stem Cells</p>

“…61,62 Moreover, EMT promotes tumor cell aggressiveness by increasing the expression of MMPs, especially gelatinases. 63 Thus, we hypothesized that Sal NPs can target cancer cells and CSCs through a gelatinasestimuli strategy. Previous studies have reported that our gelatinase-stimuli NPs showed superior performance as a delivery system for docetaxel or 5-fluorouracil.…”