Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer
Authors: Nan Kang
Tian Lan
Weimin Zhang
Kangtai Liu
Ming Fu
Lijia Dong
Shumin Zhang
Bing Liu
Qimin Zhan
Jie Chen
Journal: Cancer Research (2015)
Discipline: CLINICAL MEDICINE
Keywords: Platelet-activating factor receptor; PAFR; tumorigenesis; metastatic progression; non-small cell lung cancer
Affiliations: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Neurosurgery, Beijing Sanbo Brain Hospital; Capital Medical University, Beijing, China., Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China., National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Tsinghua University and Chinese Academy of Medical Sciences, Beijing, China., State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. .

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. 

Retracted: No

PubPeer comments:
 This paper makes use of the CAC2 cell line which was originally thought to originate from a human salivary gland adenoid cystic carcinoma. Unfortunatly it was shown in [PMID: 19557180] that CAC2 is a rat cell line. At the time this paper was published this was not yet widely known so the authors of this paper are not to be blamed for using this cell line, nevertheless the conclusions of this paper as to their relevance to adenoid cystic carcinoma are unfortunately invalidated. See the relevant [Cellosaurus entry] . ,