Skip to main content

Advertisement

SpringerLink
Log in

Increased expression of SOX4 is a biomarker for malignant status and poor prognosis in patients with non-small cell lung cancer

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The aim of the present study was to analyze the expression of sex-determining region Y-related high mobility group box 4 (SOX4) in non-small cell lung cancer (NSCLC) and its correlation with clinicopathologic characteristics, including the survival of NSCLC patients. To observe initially the expression status of SOX4 in lung squamous cell carcinoma and adenocarcinoma at gene expression omnibus. The expression of SOX4 mRNA and protein was examined in NSCLC tissues and normal lung tissues through real-time PCR and immunohistochemistry. Meanwhile, the relationship of SOX4 expression levels with clinical characteristics of 168 NSCLC patients was analyzed by immunohistochemistry. Univariate and multivariate analyses were performed to determine the association between SOX4 expression and prognosis of NSCLC patients. In our results, SOX4 expression was increased in NSCLC tissues compared with paired normal lung tissues in microarray data (GSE3268). SOX4 mRNA and protein expression were markedly higher in NSCLC tissues than in normal lung tissues (P = 0.001 and P = 0.001, respectively). Using immunohistochemistry, high levels of SOX4 protein were positively correlated with status of differentiated degree (high vs. middle, P = 0.004; high vs. low, P < 0.001), clinical stage (I–II vs. III–IV, P < 0.001), T classification (T1–T2 vs. T3–T4, P = 0.004), N classification (N0–N1 vs. N2–N3, P = 0.002), and M classification (M0 vs. M1, P = 0.011) in NSCLC. Moreover, the higher level of SOX4 expression was markedly correlated with poor overall survival in NSCLC patients (P < 0.001). Multivariate analysis suggested that increased SOX4 expression was a poor independent prognostic predictor for NSCLC patients (P = 0.002). In conclusion, SOX4 plays an important role on NSCLC progression and prognosis and may serve as a convictive prognostic biomarker for NSCLC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA: Cancer J Clin 64(1):9–29. doi:10.3322/caac.21208

    Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA: Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Google Scholar 

  3. Rosell R, Karachaliou N (2013) Lung cancer: Maintenance therapy and precision medicine in NSCLC. Nat Rev Clin Oncol 10(10):549–550. doi:10.1038/nrclinonc.2013.152

    Article  CAS  PubMed  Google Scholar 

  4. Penzo-Mendez AI (2010) Critical roles for SoxC transcription factors in development and cancer. Int J Biochem Cell Biol 42(3):425–428. doi:10.1016/j.biocel.2009.07.018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Jafarnejad SM, Ardekani GS, Ghaffari M, Li G (2013) Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis. Cell Mol Life Sci 70(15):2677–2696. doi:10.1007/s00018-012-1187-y

    Article  CAS  PubMed  Google Scholar 

  6. Schilham MW, Oosterwegel MA, Moerer P, Ya J, de Boer PA, van de Wetering M, Verbeek S, Lamers WH, Kruisbeek AM, Cumano A, Clevers H (1996) Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature 380(6576):711–714. doi:10.1038/380711a0

    Article  CAS  PubMed  Google Scholar 

  7. Schilham MW, Moerer P, Cumano A, Clevers HC (1997) Sox-4 facilitates thymocyte differentiation. Eur J Immunol 27(5):1292–1295. doi:10.1002/eji.1830270534

    Article  CAS  PubMed  Google Scholar 

  8. Cheung M, Abu-Elmagd M, Clevers H, Scotting PJ (2000) Roles of Sox4 in central nervous system development. Brain Res Mol Brain Res 79(1–2):180–191

    Article  CAS  PubMed  Google Scholar 

  9. Liao YL, Sun YM, Chau GY, Chau YP, Lai TC, Wang JL, Horng JT, Hsiao M, Tsou AP (2008) Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. Oncogene 27(42):5578–5589. doi:10.1038/onc.2008.168

    Article  CAS  PubMed  Google Scholar 

  10. Hur W, Rhim H, Jung CK, Kim JD, Bae SH, Jang JW, Yang JM, Oh ST, Kim DG, Wang HJ, Lee SB, Yoon SK (2010) SOX4 overexpression regulates the p53-mediated apoptosis in hepatocellular carcinoma: clinical implication and functional analysis in vitro. Carcinogenesis 31(7):1298–1307. doi:10.1093/carcin/bgq072

    Article  CAS  PubMed  Google Scholar 

  11. Liu P, Ramachandran S, Ali Seyed M, Scharer CD, Laycock N, Dalton WB, Williams H, Karanam S, Datta MW, Jaye DL, Moreno CS (2006) Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res 66(8):4011–4019. doi:10.1158/0008-5472.can-05-3055

    Article  CAS  PubMed  Google Scholar 

  12. Moreno CS (2010) The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. Am J Pathol 176(2):518–527. doi:10.2353/ajpath.2010.090657

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Zhang J, Liang Q, Lei Y, Yao M, Li L, Gao X, Feng J, Zhang Y, Gao H, Liu DX, Lu J, Huang B (2012) SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. Cancer Res 72(17):4597–4608. doi:10.1158/0008-5472.can-12-1045

    Article  CAS  PubMed  Google Scholar 

  14. Graham JD, Hunt SM, Tran N, Clarke CL (1999) Regulation of the expression and activity by progestins of a member of the SOX gene family of transcriptional modulators. J Mol Endocrinol 22(3):295–304

    Article  CAS  PubMed  Google Scholar 

  15. Sinner D, Kordich JJ, Spence JR, Opoka R, Rankin S, Lin SC, Jonatan D, Zorn AM, Wells JM (2007) Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol 27(22):7802–7815. doi:10.1128/mcb.02179-06

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Andersen CL, Christensen LL, Thorsen K, Schepeler T, Sorensen FB, Verspaget HW, Simon R, Kruhoffer M, Aaltonen LA, Laurberg S, Orntoft TF (2009) Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer. Br J Cancer 100(3):511–523. doi:10.1038/sj.bjc.6604884

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Aaboe M, Birkenkamp-Demtroder K, Wiuf C, Sorensen FB, Thykjaer T, Sauter G, Jensen KM, Dyrskjot L, Orntoft T (2006) SOX4 expression in bladder carcinoma: clinical aspects and in vitro functional characterization. Cancer Res 66(7):3434–3442. doi:10.1158/0008-5472.can-05-3456

    Article  CAS  PubMed  Google Scholar 

  18. Gunes S, Yegin Z, Sullu Y, Buyukalpelli R, Bagci H (2011) SOX4 expression levels in urothelial bladder carcinoma. Pathol Res Pract 207(7):423–427. doi:10.1016/j.prp.2011.05.005

    Article  CAS  PubMed  Google Scholar 

  19. Fevre-Montange M, Champier J, Szathmari A, Wierinckx A, Mottolese C, Guyotat J, Figarella-Branger D, Jouvet A, Lachuer J (2006) Microarray analysis reveals differential gene expression patterns in tumors of the pineal region. J Neuropathol Exp Neurol 65(7):675–684. doi:10.1097/01.jnen.0000225907.90052.e3

    Article  CAS  PubMed  Google Scholar 

  20. Litovkin KV, Ivanova OV, Bauer A, Hoheisel JD, Bubnov VV, Zaporozhan VN (2008) Microarray study of gene expression in uterine leiomyoma. Exp Oncol 30(2):106–111

    CAS  PubMed  Google Scholar 

  21. Cao D, Hustinx SR, Sui G, Bala P, Sato N, Martin S, Maitra A, Murphy KM, Cameron JL, Yeo CJ, Kern SE, Goggins M, Pandey A, Hruban RH (2004) Identification of novel highly expressed genes in pancreatic ductal adenocarcinomas through a bioinformatics analysis of expressed sequence tags. Cancer Biol Ther 3(11):1081–1089 discussion 1090–1081

    Article  CAS  PubMed  Google Scholar 

  22. Molatore S, Liyanarachchi S, Irmler M, Perren A, Mannelli M, Ercolino T, Beuschlein F, Jarzab B, Wloch J, Ziaja J, Zoubaa S, Neff F, Beckers J, Hofler H, Atkinson MJ, Pellegata NS (2010) Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma. Proc Natl Acad Sci USA 107(43):18493–18498. doi:10.1073/pnas.1003956107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Lin B, Madan A, Yoon JG, Fang X, Yan X, Kim TK, Hwang D, Hood L, Foltz G (2010) Massively parallel signature sequencing and bioinformatics analysis identifies up-regulation of TGFBI and SOX4 in human glioblastoma. PLoS One 5(4):e10210. doi:10.1371/journal.pone.0010210

    Article  PubMed Central  PubMed  Google Scholar 

  24. Huang YW, Liu JC, Deatherage DE, Luo J, Mutch DG, Goodfellow PJ, Miller DS, Huang TH (2009) Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res 69(23):9038–9046. doi:10.1158/0008-5472.can-09-1499

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ (2002) Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol 57(3):201–214

    Article  PubMed  Google Scholar 

  26. Frierson HF Jr, El-Naggar AK, Welsh JB, Sapinoso LM, Su AI, Cheng J, Saku T, Moskaluk CA, Hampton GM (2002) Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. Am J Pathol 161(4):1315–1323. doi:10.1016/s0002-9440(10)64408-2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Medina PP, Castillo SD, Blanco S, Sanz-Garcia M, Largo C, Alvarez S, Yokota J, Gonzalez-Neira A, Benitez J, Clevers HC, Cigudosa JC, Lazo PA, Sanchez-Cespedes M (2009) The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Hum Mol Genet 18(7):1343–1352. doi:10.1093/hmg/ddp034

    Article  CAS  PubMed  Google Scholar 

  28. Bangur CS, Switzer A, Fan L, Marton MJ, Meyer MR, Wang T (2002) Identification of genes over-expressed in small cell lung carcinoma using suppression subtractive hybridization and cDNA microarray expression analysis. Oncogene 21(23):3814–3825. doi:10.1038/sj.onc.1205480

    Article  CAS  PubMed  Google Scholar 

  29. Li J, Guan HY, Gong LY, Song LB, Zhang N, Wu J, Yuan J, Zheng YJ, Huang ZS, Li M (2008) Clinical significance of sphingosine kinase-1 expression in human astrocytomas progression and overall patient survival. Clin Cancer Res 14(21):6996–7003. doi:10.1158/1078-0432.ccr-08-0754

    Article  CAS  PubMed  Google Scholar 

  30. Vervoort SJ, van Boxtel R, Coffer PJ (2013) The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? Oncogene 32(29):3397–3409. doi:10.1038/onc.2012.506

    Article  CAS  PubMed  Google Scholar 

  31. Pramoonjago P, Baras AS, Moskaluk CA (2006) Knockdown of Sox4 expression by RNAi induces apoptosis in ACC3 cells. Oncogene 25(41):5626–5639. doi:10.1038/sj.onc.1209566

    Article  CAS  PubMed  Google Scholar 

  32. Vervoort SJ, Lourenco AR, van Boxtel R, Coffer PJ (2013) SOX4 mediates TGF-beta-induced expression of mesenchymal markers during mammary cell epithelial to mesenchymal transition. PLoS One 8(1):e53238. doi:10.1371/journal.pone.0053238

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Haram KM, Peltier HJ, Lu B, Bhasin M, Otu HH, Choy B, Regan M, Libermann TA, Latham GJ, Sanda MG, Arredouani MS (2008) Gene expression profile of mouse prostate tumors reveals dysregulations in major biological processes and identifies potential murine targets for preclinical development of human prostate cancer therapy. Prostate 68(14):1517–1530. doi:10.1002/pros.20803

    Article  CAS  PubMed  Google Scholar 

  34. Wang C, Zhao H, Lu J, Yin J, Zang L, Song N, Dong R, Wu T, Du X (2012) Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma. Diagn Pathol 7:41. doi:10.1186/1746-1596-7-41

    Article  PubMed Central  PubMed  Google Scholar 

  35. Jafarnejad SM, Wani AA, Martinka M, Li G (2010) Prognostic significance of Sox4 expression in human cutaneous melanoma and its role in cell migration and invasion. Am J Pathol 177(6):2741–2752. doi:10.2353/ajpath.2010.100377

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Shen R, Pan S, Qi S, Lin X, Cheng S (2010) Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. Biochem Biophys Res Commun 394(4):1047–1052. doi:10.1016/j.bbrc.2010.03.121

    Article  CAS  PubMed  Google Scholar 

  37. Ramezani-Rad P, Geng H, Hurtz C, Chan LN, Chen Z, Jumaa H, Melnick A, Paietta E, Carroll WL, Willman CL, Lefebvre V, Muschen M (2013) SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood 121(1):148–155. doi:10.1182/blood-2012-05-428938

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

None.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Xianning Central Hospital, Xianning, 437100, Hubei, China

    Dingmiao Wang, Ting Hao, Yang Pan & Xiaowei Qian

  2. Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, Hubei, China

    Daixing Zhou

Authors
  1. Dingmiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ting Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaowei Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daixing Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daixing Zhou.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, D., Hao, T., Pan, Y. et al. Increased expression of SOX4 is a biomarker for malignant status and poor prognosis in patients with non-small cell lung cancer. Mol Cell Biochem 402, 75–82 (2015). https://doi.org/10.1007/s11010-014-2315-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2315-9

Keywords

Search

Navigation