PLEK2 mediates metastasis and vascular invasion via the ubiquitin-dependent degradation of SHIP2 in non-small cell lung cancer.
Metastasis is the leading cause of death for non-small cell lung cancer (NSCLC) patients. However, how lung cancer cells invade blood vessels during metastasis remains unclear. Here, based on bioinformatics analyses, we found that PLEK2 might regulate NSCLC migration and vascular invasion. As little is known about the function of ... PLEK2 in NSCLC, we aimed to clarify this. We demonstrated that PLEK2 was significantly upregulated in transforming growth factor beta 1 (TGF-?1)-treated NSCLC cells through ELK1 transcriptional activation, highly expressed in NSCLC tissues, and negatively correlated with NSCLC overall survival. Meanwhile, PLEK2 overexpression significantly promoted NSCLC epithelial-to-mesenchymal transition (EMT) and migration, human lung microvascular endothelial cells endothelial-to-mesenchymal transition (EndoMT), and the destruction of vascular endothelial barriers. Moreover, PLEK2 knockdown inhibited TGF-?1-induced EMT and EndoMT. Furthermore, PLEK2 was found to directly interact with SHIP2 and target it for ubiquitination and degradation in NSCLC cells. Next, we confirmed that SHIP2 overexpression inhibits NSCLC EMT, migration and invasion and showed that PLEK2 overexpression can activate SHIP2-associated TGF-?/PI3K/AKT signaling. Our results suggest that PLEK2 could be a novel prognostic marker and potential therapeutic target for NSCLC metastasis and vascular invasion.
Mesh Terms:
Animals, Apoptosis, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Endothelium, Vascular, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Membrane Proteins, Mice, Mice, Nude, Neoplasm Invasiveness, Phosphatidylinositol 3-Kinases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Prognosis, Proteolysis, Proto-Oncogene Proteins c-akt, Tumor Cells, Cultured, Ubiquitin, Xenograft Model Antitumor Assays
Animals, Apoptosis, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Endothelium, Vascular, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Membrane Proteins, Mice, Mice, Nude, Neoplasm Invasiveness, Phosphatidylinositol 3-Kinases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Prognosis, Proteolysis, Proto-Oncogene Proteins c-akt, Tumor Cells, Cultured, Ubiquitin, Xenograft Model Antitumor Assays
Int J Cancer
Date: May. 01, 2020
PubMed ID: 31498891
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