title: Cyclooxygenase-2 induced β1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway.
abstract: Cyclooxygenase-2 (COX-2) has been implicated in cell invasion in non-small-cell lung cancer (NSCLC). However, the mechanism is unclear. The present study investigated the effect of COX-2 on β1-integrin expression and cell invasion in NSCLC. COX-2 and β1-integrin were co-expressed in NSCLC tissues. COX-2 overexpression or Prostaglandin E2 (PGE2) treatment increased β1-integrin expression in NSCLC cell lines. β1-integrin silencing suppressed COX-2-mediated tumour growth and cancer cell invasion in vivo and in vitro. Prostaglandin E Receptor EP1 transfection or treatment with EP1 agonist mimicked the effect of PGE2treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. EP1 agonist treatment promoted Erk1/2, p38 phosphorylation and E2F-1 expression. MEK1/2 and p38 inhibitors suppressed EP1-mediated β1-integrin expression. E2F-1 silencing suppressed EP1-mediated FoxC2 and β1-integrin upregulation. ChIP and Luciferase Reporter assays identified that EP1 agonist treatment induced E2F-1 binding to FoxC2 promotor directly and improved FoxC2 transcription. FoxC2 siRNA suppressed β1-integrin expression and EP1-mediated cell invasion. Immunohistochemistry showed E2F-1, FoxC2, and EP1R were all highly expressed in the NSCLC cases. This study suggested that COX-2 upregulates β1-integrin expression and cell invasion in NSCLC by activating the MAPK/E2F-1 signalling pathway. Targeting the COX-2/EP1/PKC/MAPK/E2F-1/FoxC2/β1-integrin pathway might represent a new therapeutic strategy for the prevention and treatment of this cancer.
authors.affiliation: Department of Biotherapy, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China.|Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Pathology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Qinyi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Bioinformatics, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Jiaofang
authors.initials: J
authors.lastname: Shao
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: Yipin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania PA 19107, USA.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Leng
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Bai