Neuropilin-2 Is Upregulated in Lung Cancer Cells during TGF-β1―Induced Epithelial-Mesenchymal Transition

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 23; pp. 7111 - 7121
• Main Authors: NASARRE, Patrick, GEMMILL, Robert M, DRABKIN, Harry A, POTIRON, Vincent A, ROCHE, Joëlle, XIAN LU, BARON, Anna E, KORCH, Christopher, GARRETT-MAYER, Elizabeth, LAGANA, Alessandro, HOWE, Philip H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2013
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Nude; Mice, Transgenic; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neuropilin-2 - genetics; Pharmacology. Drug treatments; Pneumology; Transforming Growth Factor beta1 - pharmacology; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum; Up-Regulation; Lung disease; Respiratory disease; Lung cancer; Bronchus disease; Malignant tumor; Transforming growth factor β1; Epithelial mesenchymal transition; Cell transformation; Bronchopulmonary; Tumor cell; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-1755

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.