Abstract
BackgroundGallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. Little is known about its invasion and metastasis mechanism so far.MethodsTo 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.ResultsIn 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.ConclusionsOn 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.
Highlights
Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate
PLEK2 was up-regulated in gallbladder cancer and correlated with poor prognosis To identify the driver genes in GBC metastasis, we made a mRNA microarray consisted of six pairs of metastatic GBC and non-tumor samples (Fig. 1a)
Analysis the gene expression differences and its distribution in human cancer cells by bioinformatics data, we found that PLEK2, one of the most upregulated genes in GBC compared with paired nontumor tissues, had a relative high expression in biliary tract cancer (Additional file 1: Figure S1A). Quantitative real time PCR (qRT-PCR) data of 29 pairs of GBC and non-cancerous adjacent tissues verified PLEK2 mRNA level was up-regulated in GBC compared with non-cancerous adjacent tissues (Fig. 1b)
Summary
Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. PLEK2 was found to play crucial roles in cancer metastasis and progression. Naume et al found PLEK2 expression was correlated with luminal A type breast cancer cells disseminating to bone marrow and the disseminated tumor cell status predicted clinical outcome [11]. A large whole blood-based transcriptome analysis identified PLEK2 expression was the strongest gene to distinguish CD45− subsets melanoma patients from healthy people. Transcriptome profiling of PLEK2 expression in whole blood cells could be used as early detection of melanoma [12]. The role of PLEK2 in tumor metastasis is being recognized gradually, but the clear mechanism of how it works is poorly understood. To our knowledge, the role of PLEK2 in GBC has not been studied before
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