title: Neuropilin-2 Is upregulated in lung cancer cells during TGF-β1-induced epithelial-mesenchymal transition.
abstract: The epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET), are fundamental processes involved in tumor cell invasion and metastasis. SEMA3F is a secreted semaphorin and tumor suppressor downregulated by TGF-β1 and ZEB1-induced EMT. Here, we report that neuropilin (NRP)-2, the high-affinity receptor for SEMA3F and a coreceptor for certain growth factors, is upregulated during TGF-β1-driven EMT in lung cancer cells. Mechanistically, NRP2 upregulation was TβRI dependent and SMAD independent, occurring mainly at a posttranscriptional level involving increased association of mRNA with polyribosomes. Extracellular signal-regulated kinase (ERK) and AKT inhibition blocked NRP2 upregulation, whereas RNA interference-mediated attenuation of ZEB1 reduced steady-state NRP2 levels. In addition, NRP2 attenuation inhibited TGF-β1-driven morphologic transformation, migration/invasion, ERK activation, growth suppression, and changes in gene expression. In a mouse xenograft model of lung cancer, NRP2 attenuation also inhibited locally invasive features of the tumor and reversed TGF-β1-mediated growth inhibition. In support of these results, human lung cancer specimens with the highest NRP2 expression were predominantly E-cadherin negative. Furthermore, the presence of NRP2 staining strengthened the association of E-cadherin loss with high-grade tumors. Together, our results demonstrate that NRP2 contributes significantly to TGF-β1-induced EMT in lung cancer.
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Public Health Sciences, Department of Biochemistry, The Hollings Cancer Center and Medical University of South Carolina, Charleston, South Carolina; Department of Biostatistics and informatics; Division of Medical Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado; and Department of Molecular Virology, Immunology, and Medical Genetics, School of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nasarre
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gemmill
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Potiron
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roche
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Christopher
authors.initials: C
authors.lastname: Korch
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lagana
authors.forename: Philip H
authors.initials: PH
authors.lastname: Howe
authors.forename: Harry A
authors.initials: HA
authors.lastname: Drabkin
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D039943:Neuropilin-2 / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D039943:Neuropilin-2; D053773:Transforming Growth Factor beta1; C581308:neuropilin-2, human