NAV2 facilitates invasion of cutaneous melanoma cells by targeting SNAI2 through the GSK-3β/β-catenin pathway

  • Wei Hu
  • Xiaoqing Li
  • Ruimin Cheng
  • Jingru Ke
  • Yamei Liu
  • Menglan Ma
  • Yuchun CaoEmail author
  • Dongxian LiuEmail author
Original Paper


Previous studies have identified neuron navigator 2(NAV2) as an oncogene in several human tumors. However, the NAV2 gene expression changes and its role in the pathogenesis of cutaneous melanoma have not been clearly illustrated. Further investigations of NAV2 in cutaneous melanoma may provide new mechanistic insight and treatment strategy for this disease. Through immunohistochemistry assay and bioinformatics analysis, we found that melanoma tissues showed an upregulated expression of NAV2 which correlated with poor prognosis of cutaneous melanoma. To investigate the effect of NAV2 on the proliferation and invasion of melanoma, shNAV2 and NAV2-cDNA were transfected into melanoma cell lines. NAV2 overexpression significantly promoted melanoma cell proliferation, migration and invasion, while NAV2 silencing effectively inhibited this process. The potential underlying mechanisms were investigated using bioinformatics analysis, qRT-PCR, and western blot. Results showed that NAV2-mediated invasion of melanoma cells was driven by enhanced epithelial–mesenchymal transition, which was resulted from SNAI2 upregulation via the GSK-3β/β-catenin pathway. This study suggested that NAV2 could induce melanoma proliferation and invasion by epithelial–mesenchymal transition through the GSK-3β/β-catenin-SNAI2 pathway. Our findings on the pathological mechanisms of NAV2-associated cutaneous melanoma may contribute to the development of potential therapeutic strategy for melanoma.


NAV2 Melanoma SNAI2 Epithelial-to-mesenchymal transition Bioinformatics analysis 



Neuron navigator


Skin cutaneous melanoma


Epithelial–mesenchymal transition


Snail homolog 2


Gene ontology


Kyoto encyclopedia of genes and genomes



We acknowledge all the colleagues who participated in this study.


This work was supported by the National Natural Science Foundation of China (No.81472000).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were approved by the Ethics Committee of Tongji hospital and in accordance with the declaration of Helsinki.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

403_2019_1909_MOESM1_ESM.pdf (513 kb)
Supplementary material 1 (PDF 513 KB)


  1. 1.
    Alves CL, Elias D, Lyng MB, Bak M, Ditzel HJ (2018) SNAI2 upregulation is associated with an aggressive phenotype in fulvestrant-resistant breast cancer cells and is an indicator of poor response to endocrine therapy in estrogen receptor-positive metastatic breast cancer. Breast Cancer Res 20:60. CrossRefGoogle Scholar
  2. 2.
    Carlsson E, Krohn K, Ovaska K, Lindberg P, Hayry V, Maliniemi P, Lintulahti A, Korja M, Kivisaari R, Hussein S, Haapasalo H, Ranki A (2013) Neuron navigator 3 alterations in nervous system tumors associate with tumor malignancy grade and prognosis. Genes Chromosom Cancer 52:191–201. CrossRefGoogle Scholar
  3. 3.
    Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM (1999) The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 18:2883–2891. CrossRefGoogle Scholar
  4. 4.
    Davidson B, Hellesylt E, Holth A, Danielsen HE, Skeie-Jensen T, Katz B (2017) Neuron navigator-2 and cyclin D2 are new candidate prognostic markers in uterine sarcoma. Virchows Arch 471:355–362. CrossRefGoogle Scholar
  5. 5.
    Fenouille N, Tichet M, Dufies M, Pottier A, Mogha A, Soo JK, Rocchi S, Mallavialle A, Galibert MD, Khammari A, Lacour JP, Ballotti R, Deckert M, Tartare Deckert S (2012) The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS One 7:e40378. CrossRefGoogle Scholar
  6. 6.
    Gong F, Guo Y, Niu Y, Jin J, Zhang X, Shi X, Zhang L, Li R, Chen L, Ma RZ (2017) Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma. Oncotarget 8:315–328. Google Scholar
  7. 7.
    Gonzalez DM, Medici D (2014) Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 7:re8. CrossRefGoogle Scholar
  8. 8.
    Gu Y, Wang Z, Shi J, Wang L, Hou Z, Guo X, Tao Y, Wu X, Zhou W, Liu Y, Zhang W, Xu Y, Yang H, Xue F, Geng D (2017) Titanium particle-induced osteogenic inhibition and bone destruction are mediated by the GSK-3beta/beta-catenin signal pathway. Cell Death Dis 8:e2878. CrossRefGoogle Scholar
  9. 9.
    Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998) Downregulation of β-catenin by human axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr Biol 8:573–581. CrossRefGoogle Scholar
  10. 10.
    Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154:8–20CrossRefGoogle Scholar
  11. 11.
    Ishiguro H, Shimokawa T, Tsunoda T, Tanaka T, Fujii Y, Nakamura Y, Furukawa Y (2002) Isolation of HELAD1, a novel human helicase gene up-regulated in colorectal carcinomas. Oncogene 21:6387–6394.
  12. 12.
    Ju J, Chen A, Deng Y, Liu M, Wang Y, Wang Y, Nie M, Wang C, Ding H, Yao B, Gui T, Li X, Xu Z, Ma C, Song Y, Kvansakul M, Zen K, Zhang CY, Luo C, Fang M, Huang DCS, Allis CD, Tan R, Zeng CK, Wei J, Zhao Q (2017) NatD promotes lung cancer progression by preventing histone H4 serine phosphorylation to activate Slug expression. Nat Commun 8:928. CrossRefGoogle Scholar
  13. 13.
    Kao SH, Wang WL, Chen CY, Chang YL, Wu YY, Wang YT, Wang SP, Nesvizhskii AI, Chen YJ, Hong TM, Yang PC (2014) GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug. Oncogene 33:3172–3182. CrossRefGoogle Scholar
  14. 14.
    Maes T, Barcelo A, Buesa C (2002) Neuron navigator: a human gene family with homology to unc-53, a cell guidance gene from Caenorhabditis elegans. Genomics 80:21–30. CrossRefGoogle Scholar
  15. 15.
    Muley PD, McNeill EM, Marzinke MA, Knobel KM, Barr MM, Clagett-Dame M (2008) The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation. Dev Neurobiol 68:1441–1453. CrossRefGoogle Scholar
  16. 16.
    Pandey A, Yadav V, Sharma A, Khurana JP, Pandey GK (2018) The unc-53 gene negatively regulates rac GTPases to inhibit unc-5 activity during Distal tip cell migrations in C. elegans. Cell Adh Migr 12:195–203. CrossRefGoogle Scholar
  17. 17.
    Savagner P, Yamada KM, Thiery JP (1997) The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol 137:1403–1419. CrossRefGoogle Scholar
  18. 18.
    Schmidt KL, Marcus-Gueret N, Adeleye A, Webber J, Baillie D, Stringham EG (2009) The cell migration molecule UNC-53/NAV2 is linked to the ARP2/3 complex by ABI-1. Development 136:563–574. CrossRefGoogle Scholar
  19. 19.
    Shirley SH, Greene VR, Duncan LM, Torres Cabala CA, Grimm EA, Kusewitt DF (2012) Slug expression during melanoma progression. Am J Pathol 180:2479–2489. CrossRefGoogle Scholar
  20. 20.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. CrossRefGoogle Scholar
  21. 21.
    Srivastava K, Pickard A, Craig SG, Quinn GP, Lambe SM, James JA, McDade SS, McCance DJ (2018) DeltaNp63gamma/SRC/Slug signaling axis promotes epithelial-to-mesenchymal transition in squamous cancers. Clin Cancer Res 24:3917–3927. CrossRefGoogle Scholar
  22. 22.
    Stringham E, Pujol N, Vandekerckhove J, Bogaert T (2002) unc-53 controls longitudinal migration in C. elegans. Development 129:3367–3379.
  23. 23.
    Stringham EG, Schmidt KL (2009) Navigating the cell: UNC-53 and the navigators, a family of cytoskeletal regulators with multiple roles in cell migration, outgrowth and trafficking. Cell Adh Migr 3:342–346. CrossRefGoogle Scholar
  24. 24.
    Tan F, Zhu H, Tao Y, Yu N, Pei Q, Liu H, Zhou Y, Xu H, Song X, Li Y, Zhou Z, He X, Zhang X, Pei H (2015) Neuron navigator 2 overexpression indicates poor prognosis of colorectal cancer and promotes invasion through the SSH1L/cofilin-1 pathway. J Exp Clin Cancer Res 34:117. CrossRefGoogle Scholar
  25. 25.
    Tront JS, Huang Y, Fornace AJ Jr, Hoffman B, Liebermann DA (2010) Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress. Cancer Res 70:9671–9681. CrossRefGoogle Scholar
  26. 26.
    Wang ZY, Hu M, Dai MH, Xiong J, Zhang S, Wu HJ, Zhang SS, Gong ZJ (2018) Upregulation of the long non-coding RNA AFAP1-AS1 affects the proliferation, invasion and survival of tongue squamous cell carcinoma via the Wnt/beta-catenin signaling pathway. Mol Cancer 17:3. CrossRefGoogle Scholar
  27. 27.
    Yang Y, Liu Y, He JC, Wang JM, Schemmer P, Ma CQ, Qian YW, Yao W, Zhang J, Qi WP, Fu Y, Feng W, Yang T (2016) 14-3-3zeta and aPKC-iota synergistically facilitate epithelial-mesenchymal transition of cholangiocarcinoma via GSK-3beta/Snail signaling pathway. Oncotarget 7:55191–55210. Google Scholar
  28. 28.
    Yu J, Wang X, Lu Q, Wang J, Li L, Liao X, Zhu W, Lv L, Zhi X, Yu J, Jin Y, Zou Q, Ou Z, Liu X, Zhou P (2018) Extracellular 5′-nucleotidase (CD73) promotes human breast cancer cells growth through AKT/GSK-3beta/beta-catenin/cyclinD1 signaling pathway. Int J Cancer 142:959–967. CrossRefGoogle Scholar
  29. 29.
    Zhao R, Li Y, Lin Z, Wan J, Xu C, Zeng Y, Zhu Y (2016) miR-199b-5p modulates BMSC osteogenesis via suppressing GSK-3beta/beta-catenin signaling pathway. Biochem Biophys Res Commun 477:749–754. CrossRefGoogle Scholar
  30. 30.
    Zou L, Chai J, Gao Y, Guan J, Liu Q, Du JJ (2016) Down-regulated PLAC8 promotes hepatocellular carcinoma cell proliferation by enhancing PI3K/Akt/GSK3beta/Wnt/beta-catenin signaling. Biomed Pharmacother 84:139–146. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Dermatology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  2. 2.Department of Nephrology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China

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