Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer

Abstract

Platelet-activating factor receptor (PAFR), a G-protein-coupled receptor, has been implicated in tumorigenesis, but its contributions to metastatic progression have not been investigated. Here, we show that PAFR is overexpressed in non-small cell lung cancer (NSCLC) as well as in breast, colorectal, and gastric carcinomas. Expression of PAFR correlates closely with clinical stages, survival time, and distant metastasis. In human NSCLC cells, activation of the PAF/PAFR signaling axis accentuated malignant character, including by stimulating epithelial-mesenchymal transition (EMT). In contrast, silencing PAFR in aggressive NSCLC cells inhibited these effects. Mechanistic investigations showed that PAFR stimulated EMT by activating STAT3 via upregulation of G-protein-dependent SRC or JAK2 kinase activity. Notably, STAT3 transcriptionally elevated PAFR expression. Thus, activation of PAFR in NSCLC cells initiated a forward feedback loop responsible for mediating the aggressive malignant character of NSCLC cells in vitro and in vivo. Reinforcing this reciprocal activation loop, PAF/PAFR signaling also upregulated IL6 expression and thereby STAT3 activation. Overall, our results elucidated an important role for PAFR dysregulation in the pathogenicity of NSCLC and unraveled a forward feedback loop between PAFR and STAT3 that acts to drive the malignant progression of NSCLC. Cancer Res; 75(19); 4198-210. Ó2015 AACR.

PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells

“…The high expression of PAFR and the corresponding ligand PAF results in the invasion and metastasis of colorectal cancer and NSCLC [10, 21]. Besides, several studies have shown that PAFR antagonists can reduce tumor metastasis in vivo [10, 21–23].…”

“…Besides, several studies have shown that PAFR antagonists can reduce tumor metastasis in vivo [10, 21–23]. In addition, the upregulation of PAFR contributes to cisplatin resistance in ovarian cancer via activating PI3K and ERK pathways that lies downstream of activated PAFR [13].…”

“…Platelet-activating factor (PAR) receptor (PAFR) is one of GPCR, which can be activated by PAR. It has been reported to promote non-small cell lung cancer (NSCLC) progression and metastasis by initiating forward feedback loop between PAFR and STAT3 [10], and contributes to the malignant development of esophageal squamous cell carcinoma by stimulating PI3K/AKT activation [11]. PAFR can also induce chemotherapy resistance in ovarian cancer through transactivating of epidermal growth factor receptor (EGFR) [12, 13].…”

Over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced non-small cell lung cancer cells through PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR

“…STAT3 is an effective target site to inhibit VEGF expression and tumor angiogenesis (20). It was found that there is a site for binding to STAT3 protein on the VEGF promoter (21).…”

Differential expression of folate receptor 1 in medulloblastoma and the correlation with clinicopathological characters and target therapeutic potential

“…The protocols for FCM analysis were based on the manufacture's recommendations and our previous work [43, 44]. In brief, Daoy and D283 cells were diluted 1 × 10 5 /ml, then treated with above agents for 8 h. The cells resuspended in 1 × binding buffer were incubated with Annexin V-FITC and PI in the dark for 20 min at room temperature, then analyzed by FACS.…”