SOX4 promotes melanoma cell migration and invasion though the activation of the NF-κB signaling pathway

Cheng,Qiong; Wu,Jinfeng; Zhang,Yaohua; Liu,Xiao; Xu,Nan; Zuo,Fuguo; Xu,Jinhua

doi:10.3892/ijmm.2017.3030

SOX4 promotes melanoma cell migration and invasion though the activation of the NF-κB signaling pathway

Authors:
- Qiong Cheng
- Jinfeng Wu
- Yaohua Zhang
- Xiao Liu
- Nan Xu
- Fuguo Zuo
- Jinhua Xu
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Affiliations: Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China, Department of Dermatology, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
Published online on: June 16, 2017 https://doi.org/10.3892/ijmm.2017.3030
Pages: 447-453
Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

SOX4 has been reported to be abnormally expressed in many types of cancer, including melanoma. However, its role in cell proliferation and metastasis remains controversial. In this study, SOX4 was downregulated or overexpressed in A375, A2058 and A875 melanoma cells by siRNA or lentivirus transfection, respectively. Cell metastasis was observed by Transwell assay. In an aim to elucidate the underlying mechanisms, we determined the expression of nuclear factor-κB (NF-κB) by real-time PCR assay and western blot analysis. Our data indicated that SOX4 knockdown inhibited melanoma cell migration and invasion. In the melanoma cells in which SOX4 was downregulated, the expression levels of NF-κB/p65, matrix metalloproteinase (MMP)2 and MMP9 were suppressed at both the mRNA and protein levels. Conversely, the overexpression of SOX4 promoted melanoma cell migration and invasion. In the melanoma cells in which SOX4 was overexpressed, the expression levels of NF-κB/p65, MMP2 and MMP9 were increased at both the mRNA and protein level. On the whole, our findings indicate that SOX4 promotes melanoma cell migration and invasion through the activation of the NF-κB/p65 signaling pathway. Thus, SOX4 may prove to be a potential therapeutic target for the treatment of melanoma.

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1	Romano S, Xiao Y, Nakaya M, D'Angelillo A, Chang M, Jin J, Hausch F, Masullo M, Feng X, Romano MF, et al: FKBP51 employs both scaffold and isomerase functions to promote NF-κB activation in melanoma. Nucleic Acids Res. 43:6983–6993. 2015. View Article : Google Scholar : PubMed/NCBI
2	Peterson M, Albertini MR and Remington P: Incidence, Survival, and Mortality of Malignant Cutaneous Melanoma in Wisconsin, 1995–2011. WMJ. 114:196–201. 2015.
3	Zehavi L, Schayek H, Jacob-Hirsch J, Sidi Y, Leibowitz-Amit R and Avni D: MiR-377 targets E2F3 and alters the NF-κB signaling pathway through MAP3K7 in malignant melanoma. Mol Cancer. 14:682015. View Article : Google Scholar
4	Li J, Zhang Z and Li G: Patient outcome prediction using multiple biomarkers in human melanoma: A clinicopathological study of 118 cases. Exp Ther Med. 2:131–135. 2011.PubMed/NCBI
5	Gajos-Michniewicz A and Czyz M: Modulation of WNT/β-catenin pathway in melanoma by biologically active components derived from plants. Fitoterapia. 109:283–292. 2016. View Article : Google Scholar : PubMed/NCBI
6	Webter MR, Kuqel CH III and Weeraratna AT: The Wnts of change: How Wnts regulate phenotype switching in melanoma. Biochim Biophys Acta. 1856:244–251. 2015.
7	Daphu I, Horn S, Stieber D, Varughese JK, Spriet E, Dale HA, Skaftnesmo KO, Bjerkvig R and Thorsen F: In vitro treatment of melanoma brain metastasis by simultaneously targeting the MAPK and PI3K signaling pathways. Int J Mol Sci. 15:8773–8794. 2014. View Article : Google Scholar : PubMed/NCBI
8	Yajima I, Kumasaka MY, Thang ND, Goto Y, Takeda K, Yamanoshita O, Iida M, Ohgami N, Tamura H, Kawamoto Y, et al: RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling in malignant melanoma progression and therapy. Dermatol Res Pract. 2012:3541912012.
9	Hu S, Luo Q, Cun B, Hu D, Ge S, Fan X and Chen F: The pharmacological NF-κB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells. Int J Mol Sc. 13:15653–15667. 2012. View Article : Google Scholar
10	Wu ZY, Lien JC, Huang YP, Liao CL, Lin JJ, Fan MJ, Ko YC, Hsiao YP, Lu HF and Chung JG: Casticin inhibits A375.S2 human melanoma cell migration/invasion through downregulating NF-κB and matrix metalloproteinase-2 and -1. Molecules. 21:3842016. View Article : Google Scholar
11	Li Y, Zu L, Wang Y, Wang M, Chen P and Zhou Q: miR-132 inhibits lung cancer cell migration and invasion by targeting SOX4. J Thorac Dis. 7:1563–1569. 2015.PubMed/NCBI
12	Song GD, Sun Y, Shen H and Li W: SOX4 overexpression is a novel biomarker of malignant status and poor prognosis in breast cancer patients. Tumour Biol. 36:4167–4173. 2015. View Article : Google Scholar : PubMed/NCBI
13	Zhang J, Liang Q, Lei Y, Yao M, Li L, Gao X, Feng J, Zhang Y, Gao H, Liu DX, et al: SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. Cancer Res. 72:4597–4608. 2012. View Article : Google Scholar : PubMed/NCBI
14	Wang L, Zhang J, Yang X, Chang YW, Qi M, Zhou Z, Zhang J and Han B: SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial-mesenchymal transition in vitro. Prostate Cancer Prostatic Dis. 16:301–307. 2013. View Article : Google Scholar : PubMed/NCBI
15	Vervoort SJ, van Boxtel R and Coffer PJ: The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: Friend or foe? Oncogene. 32:3397–3409. 2013. View Article : Google Scholar
16	Aaboe M, Birkenkamp-Demtroder K, Wiuf C, Sørensen FB, Thykjaer T, Sauter G, Jensen KM, Dyrskjøt L and Ørntoft T: SOX4 expression in bladder carcinoma: Clinical aspects and in vitro functional characterization. Cancer Res. 66:3434–3442. 2006. View Article : Google Scholar : PubMed/NCBI
17	Jafarnejad SM, Wani AA, Martinka M and Li G: Prognostic significance of Sox4 expression in human cutaneous melanoma and its role in cell migration and invasion. Am J Pathol. 177:2741–2752. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wang C, Zhao H, Lu J, Yin J, Zang L, Song N, Dong R, Wu T and Du X: Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma. Diagn Pathol. 7:412012. View Article : Google Scholar : PubMed/NCBI
19	Harris ML, Baxter LL, Loftus SK and Pavan WJ: Sox proteins in melanocyte development and melanoma. Pigment Cell Melanoma Res. 23:496–513. 2010. View Article : Google Scholar : PubMed/NCBI
20	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci USA. 101:9309–9314. 2004. View Article : Google Scholar : PubMed/NCBI
21	Lefebvre V and Bhattaram P: SOXC genes and the control of skeletogenesis. Curr Osteoporos Rep. 14:32–38. 2016. View Article : Google Scholar : PubMed/NCBI
22	Zhang J, Jiang H, Shao J, Mao R, Liu J, Ma Y, Fang X, Zhao N, Zheng S and Lin B: SOX4 inhibits GBM cell growth and induces G0/G1 cell cycle arrest through Akt-p53 axis. BMC Neurol. 14:2072014. View Article : Google Scholar : PubMed/NCBI
23	Kumar A, Takada Y, Boriek AM and Aggarwal BB: Nuclear factor-kappaB: Its role in health and disease. J Mol Med (Berl). 82:434–448. 2004. View Article : Google Scholar
24	Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K and Fisher PB: Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: Implications for tumor progression and metastasis. Cancer Res. 66:1509–1516. 2006. View Article : Google Scholar : PubMed/NCBI
25	Aggarwal BB and Sung B: NF-κB in cancer: A matter of life and death. Cancer Discov. 1:469–471. 2011. View Article : Google Scholar
26	Amiri KI and Richmond A: Role of nuclear factor-kappa B in melanoma. Cancer Metastasis Rev. 24:301–313. 2005. View Article : Google Scholar : PubMed/NCBI
27	Ryu B, Kim DS, Deluca AM and Alani RM: Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression. PLoS One. 2:e5942007. View Article : Google Scholar : PubMed/NCBI
28	Kim A, Kim MJ, Yang Y, Kim JW, Yeom YI and Lim JS: Suppression of NF-kappaB activity by NDRG2 expression attenuates the invasive potential of highly malignant tumor cells. Carcinogenesis. 30:927–936. 2009. View Article : Google Scholar : PubMed/NCBI
29	Hong IK, Kim YM, Jeoung DI, Kim KC and Lee H: Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells. Exp Mol Med. 37:230–239. 2005. View Article : Google Scholar : PubMed/NCBI
30	Seftor RE, Seftor EA, Koshikawa N, Meltzer PS, Gardner LM, Bilban M, Stetler-Stevenson WG, Quaranta V and Hendrix MJ: Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res. 61:6322–6327. 2001.PubMed/NCBI