Abstract 5154: Semaphorin 6A attenuates the migration capability of lung cancer cells via the NRF2/HMOX1 axis

Abstract

Abstract Cell migration is a fundamental feature of cancer recurrence. Since recurrence is correlated with high mortality in lung cancer, it follows that reducing cell migration would decrease recurrence and increase survival rates. The goal of this study was to determine the role of SEMA6A in cell migration. Semaphorin 6A (SEMA6A), a protein initially known as a regulator of axonal guidance, is down-regulated in lung cancer tissue, and low levels of SEMA6A are associated with cancer recurrence. Thus, we hypothesized that SEMA6A could suppress cancer cell migration. In this study, we found that the migration capability of H1299 lung cancer cells decreased with SEMA6A overexpression, while it increased with SEMA6A silencing. Reduction in migration was observed only with the full length protein and not with the extracellular ectodomain construct, suggesting that a reverse signaling mechanism is used to mediate the effects of SEMA6A on migration. Moreover, silencing of the cellular homeostasis protein HMOX1 and/or the transcription factor NRF2 reversed the migration-suppressing effect of SEMA6A and the SEMA6A-driven alterations in expression of PLAU and IGFBP3, both downstream effectors of HMOX1. Taken together, these results demonstrate that SEMA6A is a potential suppressor of migration that functions through the NRF2/HMOX1 axis. Our results explain why low SEMA6A is linked to high recurrence in the clinical setting and suggest that SEMA6A could be useful as a biomarker or target in lung cancer therapy. Citation Format: Li-Han Chen, Che-Yu Liao, Eric Y. Chuang, Mong-Hsun Tsai. Semaphorin 6A attenuates the migration capability of lung cancer cells via the NRF2/HMOX1 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5154.