Abstract 2416: Neuropilin-2 is upregulated during EMT in lung cancer

Abstract

Abstract Neuropilins (NRP1 and NRP2) are high affinity receptors for the class-3 semaphorins, cell guidance molecules involved in tissue development, immune responses, angiogenesis and cancer. Semaphorins affect cell protrusion, spreading and adhesion, and can trigger migratory responses often in a repulsive manner depending on the cellular context. Interestingly, neuropilins are also receptors for galectin-1 and growth factors including VEGF, PlGF, EGF and TGFβ. We previously cloned the SEMA3F gene from chromosome 3p21.3, which undergoes homozygous deletion and frequent loss of heterozygosity in lung cancer. We found that SEMA3F levels were inversely correlated with tumor aggressiveness in human lung cancer and confirmed its tumor suppressor activity in experimental xenograft models. We subsequently discovered that SEMA3F is directly downregulated by ZEB1, a transcription factor involved in the epithelial to mesenchymal transition (EMT). In the present study, we asked whether SEMA3F specific receptor, NRP2, was also regulated during the EMT process. TGFβ, a physiologic EMT inducer, stimulated NRP2 expression in two NSCLC cell lines. Forced expression of ZEB1, but not Snail, also induced NRP2. Conversely, ZEB1 and Snail inhibition blocked NRP2 upregulation by TGFβ. Importantly, inhibiting NRP2 or ZEB1 expression reduced TGFβ-induced migration in an equivalent manner. In lung cancer tissue microarrays, NRP1 and NRP2 were preferentially expressed in the tumor compartment, whereas the EMT-related transcription factors, ZEB1 and Snail, were predominantly expressed in the stroma. Of note, NRP2 was also expressed in stromal cells and was significantly associated with both ZEB1 and a higher (worse) tumor grade. Since NRP2 is the highest affinity receptor for SEMA3F, our results suggest that loss of SEMA3F coupled with increased NRP2 would facilitate the binding of growth factors to NRP2 to further promote EMT and metastasis. Therefore, targeting NRP2 could be an important therapeutic approach against EMT in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2416. doi:1538-7445.AM2012-2416