title: Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway.
abstract: Prostaglandin E2 (PGE2) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased β1-integrin expression and cell migration; however, the mechanism remains unclear. PGE2 exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1-4). The present study investigated the effect of EP1 receptor activation on β1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE2 (EP1 agonist), which was suppressed by pretreatment with a β1-integrin polyclonal antibody. PGE2 increased β1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE2 mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. 17-PT-PGE2 treatment induced PKC and NF-κB activation; PKC and NF-κB inhibitors suppressed 17-PT-PGE2-mediated β1-integrin expression. FoxC2, a β1-integrin transcription factor, was also upregulated by 17-PT-PGE2. NF-κB inhibitor suppressed 17-PT-PGE2-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and β1-integrin were all highly expressed in the HCC cases. This study suggested that PGE2 upregulates β1-integrin expression and cell migration in HCC cells by activating the PKC/NF-κB signaling pathway. Targeting PGE2/EP1/PKC/NF-κB/FoxC2/β1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pathology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Pediatrics, Fourth Clinical Medical College, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Pan
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Qinyi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Periodontal, Institute of Stomatology, The Stomatological Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shu
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Leng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019012:Integrin beta1; D016328:NF-kappa B; D058306:Receptors, Prostaglandin E, EP1 Subtype; D011493:Protein Kinase C; D015232:Dinoprostone