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PLEK2 mediates metastasis and vascular invasion via the ubiquitin‐dependent degradation of SHIP2 in non‐small cell lung cancer
Author(s) -
Wu DongMing,
Deng ShiHua,
Zhou Jin,
Han Rong,
Liu Teng,
Zhang Ting,
Li Jing,
Chen JianPing,
Xu Ying
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32675
Subject(s) - cancer research , metastasis , epithelial–mesenchymal transition , lung cancer , downregulation and upregulation , gene knockdown , pi3k/akt/mtor pathway , biology , protein kinase b , cell migration , ubiquitin , cancer , medicine , signal transduction , cell , pathology , apoptosis , microbiology and biotechnology , biochemistry , genetics , gene
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‐β1)‐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‐β1‐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‐β/PI3K/AKT signaling. Our results suggest that PLEK2 could be a novel prognostic marker and potential therapeutic target for NSCLC metastasis and vascular invasion.