title: Platelet-activating factor receptor-mediated PI3K/AKT activation contributes to the malignant development of esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide and occurs at a relatively high frequency in China, yet the mechanisms underlying its devastating outcome remain unclear. Here we report that platelet-activating factor receptor (PAFR), a type of G-protein-coupled receptor, was upregulated in ESCC tumors and cell lines, compared with controls; PAFR levels were positively correlated with ESCC clinical stages and survival time. Overexpression of PAFR promoted the malignant development of ESCC in vitro and in vivo, whereas depletion of PAFR suppressed these effects. Interestingly, PAFR was observed to activate PI3K/AKT (phosphatidylinositol 3-kinase/AKT) through the upregulation of FAK kinase activity. AKT-triggered nuclear factor-κB transcriptionally activated PAFR expression. This mutual positive regulation between PAFR and AKT was required for the aggressiveness of ESCC cells both in vitro and in vivo. Furthermore, treating mice bearing ESCC tumors with cholesterol-conjugated PAFR small interfering RNA effectively inhibited tumor progression and the expression of AKT-mediated oncogenic proteins. Taken together, we made the first demonstration that dysregulation of PAFR and the positive regulatory loop between PAFR and pAKT contribute to malignant progression of ESCC.
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: J
authors: J
authors: Chen
authors: 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.
authors: T
authors: T
authors: Lan
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: W
authors: W
authors: Zhang
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: L
authors: L
authors: Dong
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: N
authors: N
authors: Kang
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: S
authors: S
authors: Zhang
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: M
authors: M
authors: Fu
authors: Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.
authors: B
authors: B
authors: Liu
authors: 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.
authors: K
authors: K
authors: Liu
authors: Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors: C
authors: C
authors: Zhang
authors: Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors: J
authors: J
authors: Hou
authors: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Q
authors: Q
authors: Zhan
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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