Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2017 | Research

Sex-determining region Y-box protein 3 induces epithelial-mesenchymal transition in osteosarcoma cells via transcriptional activation of Snail1

Authors: Manle Qiu, Daoyun Chen, Chaoyong Shen, Ji Shen, Huakun Zhao, Yaohua He

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Abstract

Background

The transcription factor sex-determining region Y-box protein 3 (SOX3) plays important roles in various types of cancer. However, its expression and function have not yet been elucidated in osteosarcoma (OS).

Methods

The expression levels of SOX3 in OS tissues and OS cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. The effects of SOX3 expression on OS cell biological traits were investigated by overexpressing and downregulating SOX3 protein. The expression of epithelial-mesenchymal transition (EMT) markers and transcription factors associated with EMT (EMT-TFs), were detected simultaneously. The mechanism underlying SOX3-mediated Snail1 expression was further investigated.

Results

SOX3 was upregulated in human OS tissues. SOX3 overexpression promoted the EMT, migration and invasion in OS cells. The downregulation of SOX3 resulted in opposing effects. Furthermore, SOX3 upregulation enhanced the expression of the transcriptional repressor Snail1 by binding to its promoter region. Additionally, a positive correlation among the expression of SOX3, Snail1, and E-cadherin was demonstrated in human OS tissues.

Conclusions

SOX3 promotes migration, invasiveness, and EMT in OS cells via transcriptional activation of Snail1 expression, suggesting that SOX3 is a novel regulator of EMT in OS and may serve as a therapeutic target for the treatment of OS metastasis.

Jaffe N. Osteosarcoma: review of the past, impact on the future, The American experience. Cancer Treat Res. 2009;152:239–62.CrossRefPubMed

Palmerini E, Fabbri N, Staals EL, Marchesi E, Alberghini M, Tienghi A, Fagioli F, Picci P, Mercuri M, Ferrari S. Osteosarcoma of the pelvis and sacrum: a retrospective analysis of 73 patients. J Clin Oncol. 2011;29(15_suppl):10039.CrossRef

Hegyi M, Semsei AF, Jakab Z, Antal I, Kiss J, Szendroi M, Csoka M, Kovacs G. Good prognosis of localized osteosarcoma in young patients treated with limb-salvage surgery and chemotherapy. Pediatr Blood Cancer. 2011;57(3):415–22.CrossRefPubMed

Mialou V, Philip T, Kalifa C, Perol D, Gentet JC, Marec-Berard P, Pacquement H, Chastagner P, Defaschelles AS, Hartmann O. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome--the French pediatric experience. Cancer Am Cancer Soc. 2005;104(5):1100–9.

Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. 2008;68(23):9574–7.CrossRefPubMed

Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.CrossRefPubMed

Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172(7):973–81.CrossRefPubMedPubMedCentral

Larsen JE, Nathan V, Osborne JK, Farrow RK, Deb D, Sullivan JP, Dospoy PD, Augustyn A, Hight SK, Sato M, Girard L, Behrens C, Wistuba II, Gazdar AF, Hayward NK, Minna JD. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest. 2016;126(9):3219–35.CrossRefPubMedPubMedCentral

Gao Y, Xuan XY, Zhang HY, Wang F, Zeng QR, Wang ZQ, Li SS. Relationship between TWIST expression and epithelial–mesenchymal transition of oesophageal squamous cell carcinoma. Cell Biol Int. 2012;36(6):571–7.CrossRefPubMed

10.

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.CrossRefPubMedPubMedCentral

11.

Ru N, Liang J, Zhang F, Wu W, Wang F, Liu X, Du Y. SPRY4 intronic transcript 1 promotes Epithelial-mesenchymal transition through association with Snail1 in Osteosarcoma. DNA Cell Biol. 2016;35(6):290–5.CrossRefPubMed

12.

Robson EJ, Khaled WT, Abell K, Watson CJ. Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines. Differentiation. 2006;74(5):254–64.CrossRefPubMed

13.

Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004;18(10):1131–43.CrossRefPubMedPubMedCentral

14.

Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119(6):1429–37.CrossRefPubMedPubMedCentral

15.

Canesin G, Cuevas EP, Santos V, Lopez-Menendez C, Moreno-Bueno G, Huang Y, Csiszar K, Portillo F, Peinado H, Lyden D, Cano A. Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization. Oncogene. 2015;34(8):951–64.CrossRefPubMed

16.

Vidal B, Santella A, Serrano-Saiz E, Bao Z, Chuang CF, Hobert O. C. elegans SoxB genes are dispensable for embryonic neurogenesis but required for terminal differentiation of specific neuron types. Development. 2015;142(14):2464–77.CrossRefPubMedPubMedCentral

17.

Vetro A, Dehghani MR, Kraoua L, Giorda R, Beri S, Cardarelli L, Merico M, Manolakos E, Parada-Bustamante A, Castro A, Radi O, Camerino G, Brusco A, Sabaghian M, Sofocleous C, Forzano F, et al. Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3. Eur J Hum Genet. 2015;23(8):1025–32.CrossRefPubMed

18.

Bell DM, Leung KK, Wheatley SC, Ng LJ, Zhou S, Ling KW, Sham MH, Koopman P, Tam PP, Cheah KS. SOX9 directly regulates the type-II collagen gene. Nat Genet. 1997;16(2):174–8.CrossRefPubMed

19.

Fu L, Shi YB. The Sox transcriptional factors: Functions during intestinal development in vertebrates. Semin Cell Dev Biol. 2016.

20.

Yin C. Molecular mechanisms of Sox transcription factors during the development of liver, bile duct, and pancreas. Semin Cell Dev Biol. 2017;63:68–78.

21.

Uwanogho D, Rex M, Cartwright EJ, Pearl G, Healy C, Scotting PJ and Sharpe PT. Embryonic expression of the chicken Sox2, Sox3 and Sox11 genes suggests an interactive role in neuronal development. Mech Dev. 1995;49:23–36.

22.

Li K, Wang RW, Jiang YG, Zou YB, Guo W. Overexpression of Sox3 is associated with diminished prognosis in esophageal squamous cell carcinoma. Ann Surg Oncol. 2013;20 Suppl 3:S459–66.CrossRefPubMed

23.

Yan Q, Wang F, Miao Y, Wu X, Bai M, Xi X, Feng Y. Sex-determining region Y-box3 (SOX3) functions as an oncogene in promoting epithelial ovarian cancer by targeting Src kinase. Tumour Biol. 2016;37(9):12263–71.CrossRefPubMed

24.

Kim R, Trubetskoy A, Suzuki T, Jenkins NA, Copeland NG, Lenz J. Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphomas. J Virol. 2003;77(3):2056–62.CrossRefPubMedPubMedCentral

25.

Xia Y, Papalopulu N, Vogt PK, Li J. The oncogenic potential of the high mobility group box protein Sox3. Cancer Res. 2000;60(22):6303–6.PubMed

26.

Dong Y, Shen X, He M, Wu Z, Zheng Q, Wang Y, Chen Y, Wu S, Cui J, Zeng Z. Activation of the JNK-c-Jun pathway in response to irradiation facilitates Fas ligand secretion in hepatoma cells and increases hepatocyte injury. J Exp Clin Cancer Res. 2016;35(1):114.CrossRefPubMedPubMedCentral

27.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefPubMed

28.

Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608–20.CrossRefPubMed

29.

Gheldof A, Berx G. Cadherins and epithelial-to-mesenchymal transition. Prog Mol Biol Transl Sci. 2013;116:317–36.CrossRefPubMed

30.

Xu G, Guo Y, Xu D, Wang Y, Shen Y, Wang F, Lv Y, Song F, Jiang D, Zhang Y, Lou Y, Meng Y, Yang Y, Kang Y. TRIM14 regulates cell proliferation and invasion in osteosarcoma via promotion of the AKT signaling pathway. Sci Rep. 2017;7:42411.CrossRefPubMedPubMedCentral

31.

Lv YF, Dai H, Yan GN, Meng G, Zhang X, Guo QN. Downregulation of tumor suppressing STF cDNA 3 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by the Wnt/GSK-3beta/beta-catenin/Snail signaling pathway. Cancer Lett. 2016;373(2):164–73.CrossRefPubMed

32.

Guo X, Zhang J, Pang J, He S, Li G, Chong Y, Li C, Jiao Z, Zhang S, Shao M. MicroRNA-503 represses epithelial-mesenchymal transition and inhibits metastasis of osteosarcoma by targeting c-myb. Tumour Biol. 2016;37(7):9181–7.CrossRefPubMed

33.

Liu X, Liang Z, Gao K, Li H, Zhao G, Wang S, Fang J. MicroRNA-128 inhibits EMT of human osteosarcoma cells by directly targeting integrin alpha2. Tumour Biol. 2016;37(6):7951–7.CrossRefPubMed

34.

Zhou ZJ, Dai Z, Zhou SL, Hu ZQ, Chen Q, Zhao YM, Shi YH, Gao Q, Wu WZ, Qiu SJ, Zhou J and Fan J. HNRNPAB Induces Epithelial-Mesenchymal Transition and Promotes Metastasis of Hepatocellular Carcinoma by Transcriptionally Activating SNAIL. Cancer Res. 2014;74(10):2750–62.

35.

Sung JY, Park SY, Kim JH, Kang HG, Yoon JH, Na YS, Kim YN, Park BK. Interferon consensus sequence-binding protein (ICSBP) promotes epithelial-to-mesenchymal transition (EMT)-like phenomena, cell-motility, and invasion via TGF-beta signaling in U2OS cells. Cell Death Dis. 2014;5:e1224.CrossRefPubMedPubMedCentral

36.

Liu C, Lin J. Long noncoding RNA ZEB1-AS1 acts as an oncogene in osteosarcoma by epigenetically activating ZEB1. Am J Transl Res. 2016;8(10):4095–105.PubMedPubMedCentral

37.

Li M, Chen H, Zhao Y, Gao S, Cheng C. H19 Functions as a ceRNA in Promoting Metastasis Through Decreasing miR-200 s Activity in Osteosarcoma. DNA Cell Biol. 2016;35(5):235–40.CrossRefPubMed

38.

Lei P, Ding D, Xie J, Wang L, Liao Q, Hu Y. Expression profile of Twist, vascular endothelial growth factor and CD34 in patients with different phases of osteosarcoma. Oncol Lett. 2015;10(1):417–21.PubMedPubMedCentral

39.

Inoue H, Takahashi H, Hashimura M, Eshima K, Akiya M, Matsumoto T, Saegusa M. Cooperation of Sox4 with beta-catenin/p300 complex in transcriptional regulation of the Slug gene during divergent sarcomatous differentiation in uterine carcinosarcoma. BMC Cancer. 2016;16:53.CrossRefPubMedPubMedCentral

40.

Pei X, Lv X, Li H. Sox5 induces epithelial to mesenchymal transition by transactivation of Twist1. Biochem Bioph Res Co. 2014;446(1):322–7.CrossRef

41.

Wang D, Han S, Wang X, Peng R, Li X. SOX5 promotes epithelial-mesenchymal transition and cell invasion via regulation of Twist1 in hepatocellular carcinoma. Med Oncol. 2015;32(2):461.PubMed

Title: Sex-determining region Y-box protein 3 induces epithelial-mesenchymal transition in osteosarcoma cells via transcriptional activation of Snail1
Authors: Manle Qiu
Daoyun Chen
Chaoyong Shen
Ji Shen
Huakun Zhao
Yaohua He
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-017-0515-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial-mesenchymal transition

PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway

Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2.

LPS alters the immuno-phenotype of glioma and glioma stem-like cells and induces in vivo antitumor immunity via TLR4

Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter

Keynote webinar | Spotlight on antibody–drug conjugates in cancer