PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway

Abstract

Background Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. Little is known about its invasion and metastasis mechanism so far. Methods To identify the driver genes in GBC metastasis, we performed a mRNA microarray of metastatic GBC and paired non-tumor samples, and found PLEK2 was markedly upregulated in GBC tissues. Next, the expression of PLEK2 in GBC were examined in a larger cohort of patients by qRT-PCR, western blot and IHC staining. The clinicopathologic correlation of PLEK2 was determined by statistical analyses. The biological involvement of PLEK2 in GBC metastasis and the underlying mechanisms were investigated. Results In this study, we found that PLEK2 had higher expression in GBC tumor tissues compared to non-cancerous adjacent tissues and cholecystolithiasis tissues. The clinicopathologic analyses showed PLEK2 expression was positively correlated with tumor TNM stage, distant metastasis and PLEK2 was an independent predictor of overall survival (OS) in GBC patients. The cellular function assays showed PLEK2 promoted GBC cells migration, invasion and liver metastasis in mouse model via the regulation of epithelial-mesenchymal transition (EMT) process. Our mass spectrum and co-immunoprecipitation (co-IP) assays demonstrated that PLEK2 could interact with the kinase domain of EGFR and suppress EGFR ubiquitination mediated by c-CBL, leading to constitutive activation of EGFR signaling. Furthermore, RNA-sequencing and qRT-PCR results demonstrated chemokine (C-C motif) ligand 2 (CCL2), a target gene downstream of PLEK2/EGFR signaling, mediated the motility-promoting function of PLEK2. Conclusions On the basis of these collective data, we propose that PLEK2 promotes the invasion and metastasis of GBC by EGFR/CCL2 pathway and PLEK2 can serve as a potential therapeutic target for GBC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1250-8) contains supplementary material, which is available to authorized users.

Identification of UBE2T as an independent prognostic biomarker for gallbladder cancer

“…Microarray technology is commonly used to assess gene expression changes in gallbladder cancer, which was proven useful in identifying novel biomarkers ( 38 ). In the present study, 177 genes were differentially expressed in gallbladder wall tissues and tumor tissues of patients with gallbladder cancer.…”

PLEK2 Gene Upregulation Might Independently Predict Shorter Progression-Free Survival in Lung Adenocarcinoma

“… 1 - 3 It interacts with EGFR in GBC cells and promotes cell invasion and metastasis via the EGFR/CCL2 pathway. 6 PLEK2 acts as a downstream effector of the JAK2/STAT5 pathway in erythroid and myeloid cells. 19 Therefore, PLEK2 upregulation might directly lead to enhanced invasive capability of cancer cells.…”

“… 5 In gallbladder cancer (GBC), PLEK2 overexpression enhances the epithelial-mesenchymal transition (EMT) process of GBC cells and leads to a subsequent higher rate of cell migration, invasion, and liver metastasis. 6 Mechanistically, PLEK2 interact with EGFR and reduce E3 ubiquitin-protein ligase mediated EGFR ubiquitination, resulting in prolonged activation of EGFR signaling. 6 …”

“… 6 Mechanistically, PLEK2 interact with EGFR and reduce E3 ubiquitin-protein ligase mediated EGFR ubiquitination, resulting in prolonged activation of EGFR signaling. 6 …”

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

“…Plek2 expression is higher in gallbladder cancer compared to healthy adjacent tissues, where it promotes cell migration, invasion and liver metastasis in vivo, via the regulation of EMT. Mechanistically, Plek2 interacts with the kinase domain of EGFR and suppresses EGFR ubiquitination mediated by Cbl, leading to the constitutive activation of EGFR signaling [ 162 ]. All these data suggest the implication of Cbl ubiquitin-ligases in EMT by EGFR modulation in several cancer types.…”