Abstract 4969: Neuropilin-2 is downregulated by Snail during EMT in lung cancer

Abstract

Abstract Neuropilins (NRP1 and NRP2) are receptors for class-3 semaphorins that are guidance molecules involved in nerve growth patterning, tissue development, immune response, angiogenesis, and cancer development. Upon semaphorin binding, neuropilins transmit signals to the co-receptor, the plexins. Interestingly, neuropilins are also receptors for VEGF. Semaphorins control cell protrusion, spreading and adhesion and can trigger migratory responses often in a repulsive manner but also attractive depending on the cellular context. We previously cloned SEMA3F, coding for a class-3 semaphorin, in the chromosome 3p21.3 region which undergoes frequent loss of heterozygosity (LOH) in lung cancer. We further reported that levels of SEMA3F inversely correlated with tumor aggressiveness in human lung cancer and we demonstrated the tumor suppressor activity of SEMA3F in experimental xenograft models. In addition, SEMA3F is directly downregulated by ZEB1, a transcription factor involved in the epithelial to mesenchymal transition (EMT). Recently, we found an inverse correlation between the transcription factor Snail and NRP2 expression in a panel of 19 lung cancer cell lines. Interestingly, Snail is induced during EMT and NRP2 is the best affinity receptor for SEMA3F. Data will be presented with the H358 NSCLC cell line model where Snail induction decreases NRP2 expression both at the RNA and protein levels. Chromatin immunoprecipation (ChIP) experiment suggests Snail direct binding to the NRP2 promoter. In addition, in lung cancer tissue microarrays, Snail and NRP2 stainings are frequently mutually exclusive. Our results suggest that loss of SEMA3F and NRP2 would trigger EMT and promote metastasis. Therefore, targeting the semaphorin/neuropilin pathway would be an interesting therapeutic approach in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4969.