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Sci Rep. 2019 Sep 16;9(1):13302. doi: 10.1038/s41598-019-49874-8.

Semaphorin 6A Attenuates the Migration Capability of Lung Cancer Cells via the NRF2/HMOX1 Axis.

Chen LH1, Liao CY2, Lai LC3,4, Tsai MH5,6,7,8,9, Chuang EY10,11,12,13.

Author information

1
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
2
Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
3
Institute of Physiology, National Taiwan University, Taipei, Taiwan.
4
Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan.
5
Institute of Biotechnology, National Taiwan University, Taipei, Taiwan. motiont@gmail.com.
6
Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan. motiont@gmail.com.
7
Center for Biotechnology, National Taiwan University, Taipei, Taiwan. motiont@gmail.com.
8
Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan. motiont@gmail.com.
9
Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. motiont@gmail.com.
10
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan. chuangey@ntu.edu.tw.
11
Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan. chuangey@ntu.edu.tw.
12
School of Chinese Medicine, China Medical University, Taichung, Taiwan. chuangey@ntu.edu.tw.
13
Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan. chuangey@ntu.edu.tw.

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. 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. Moreover, silencing of the cellular homeostasis protein Heme-oxygenase-1 (HMOX1) and/or the transcription factor Nuclear Factor, Erythroid-2-Like-2 (NRF2) reversed the migration-suppressing effect of SEMA6A and the SEMA6A-driven alterations in expression of urokinase insulin-like-growth-factor-binding-protein-3, Matrix metalloproteinase (MMP)-1, and MMP9, the downstream effectors of HMOX1. Taken together, these results demonstrate that SEMA6A is a potential suppressor of cancer 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.

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