title: Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling.
abstract: Deregulation of Toll-like receptor 4 (TLR4) is closely associated with the progression of various types of cancers, but its role in pancreatic carcinogenesis is unclear. This study aimed to investigate the role of TLR4 in the angiogenesis of pancreatic cancer and the underlying molecular mechanisms. The culture supernatant (conditioned medium) of PANC-1 cells after appropriate treatment was used for the treatment of HUVECs. The proliferation, migration and tube formation of HUVECs were assessed by MTT, Transwell and Matrigel, respectively. In pancreatic cancer tissues, TLR4, VEGF and CD31 were upregulated as determined by immunohistochemistry and the expression of TLR4 and VEGF was positively correlated with microvessel density as detected by CD31 staining. Activation of TLR4 signaling by LPS in PANC-1 cells resulted in increased VEGF and phosphorylation of AKT, which were abolished by TLR4 silencing with siRNA and PI3K/AKT signaling inhibitor LY294002. The conditioned medium from PANC-1 cells treated with LY294002 or transfected with TRL4 siRNA reduced the proliferation, migration and tube formation of HUVECs. In contrast, the conditioned medium from PANC-1 cells treated with LPS stimulated the proliferation, migration and tube formation of HUVECs, which was however significantly inhibited by pretreatment of PANC-1 cells with LY294002 or transfection with TRL4 siRNA. Our findings suggest TLR4 may promote angiogenesis in pancreatic cancer by activating the PI3K/AKT signaling pathway to induce VEGF expression.
authors.affiliation: Department of Gastroenterology, Lianyungang Ganyu People's Hospital, Ganyu, Jiangsu, China.
authors.forename: Yunliang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, Lianyungang Ganyu People's Hospital, Ganyu, Jiangsu, China.
authors.forename: Congshan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China. Electronic address: yz_mjx@163.com.
authors.forename: Jianxia
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Man
authors.affiliation: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Shude
authors.initials: S
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Angiogenesis; PI3K/AKT signaling; Pancreatic cancer; Toll-like receptor 4; VEGF