Skip to main content
SpringerLink
Log in

Aberrant SOX2 expression in colorectal cancers does not correlate with mucinous differentiation and gastric mucin MUC5AC expression

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Colorectal cancer (CRC) can be divided into non-mucinous and mucinous subtypes, of which the latter portends to have a worse clinical prognosis. A previous study suggested a putative link between SOX2 expression observed selectively in mucinous CRC and the induction of the gastric mucin MUC5AC. In this study, we re-evaluated the expression behavior of SOX2, MUC5AC, and CDX2 in both types of CRC. We performed immunohistochemical analysis on 90 cases of non-mucinous CRCs, 57 cases of mucinous CRCs, and 15 case-matched normal intestinal mucosa. In contrast to the previously suggested link between SOX2 and mucinous CRC, we observe aberrant expression of SOX2 at equal levels in both subtypes. Fluorescence in situ hybridization (FISH) analysis shows that expression is not attributed to genomic amplification. While SOX2 and CDX2 are normally expressed in a reciprocal manner, SOX2-positive tumor cells co-express CDX2. Furthermore, we show that MUC5AC is expressed independently of SOX2. In conclusion, we show that aberrant SOX2 expression is specifically linked neither to mucinous CRCs nor to the induction of MUC5AC, in contrast to previous suggestions.

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

Similar content being viewed by others

References

  1. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50(1):113–130

    Article  PubMed  CAS  Google Scholar 

  2. Byrd JC, Bresalier RS (2004) Mucins and mucin binding proteins in colorectal cancer. Cancer Metastasis Rev 23(1–2):77–99

    Article  PubMed  CAS  Google Scholar 

  3. Verhulst J, Ferdinande L, Demetter P, Ceelen W (2012) Mucinous subtype as prognostic factor in colorectal cancer: a systematic review and meta-analysis. J Clin Pathol 65(5):381–388

    Article  PubMed  CAS  Google Scholar 

  4. Moniaux N, Andrianifahanana M, Brand RE, Batra SK (2004) Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy. Br J Cancer 91(9):1633–1638

    PubMed  CAS  PubMed Central  Google Scholar 

  5. Mukhopadhyay P, Chakraborty S, Ponnusamy MP, Lakshmanan I, Jain M, Batra SK (2011) Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. Biochim Biophys Acta 1815(2):224–240

    PubMed  CAS  PubMed Central  Google Scholar 

  6. Kufe DW (2009) Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 9(12):874–885

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Biemer-Huttmann AE, Walsh MD, McGuckin MA, Ajioka Y, Watanabe H, Leggett BA, Jass JR (1999) Immunohistochemical staining patterns of MUC1, MUC2, MUC4, and MUC5AC mucins in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum. J Histochem Cytochem 47(8):1039–1048

    Article  PubMed  CAS  Google Scholar 

  8. Biemer-Huttmann AE, Walsh MD, McGuckin MA, Simms LA, Young J, Leggett BA, Jass JR (2000) Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin Cancer Res 6(5):1909–1916

    PubMed  CAS  Google Scholar 

  9. Park ET, Gum JR, Kakar S, Kwon SW, Deng G, Kim YS (2008) Aberrant expression of SOX2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer 122(6):1253–1260

    Article  PubMed  CAS  Google Scholar 

  10. Li XL, Eishi Y, Bai YQ, Sakai H, Akiyama Y, Tani M, Takizawa T, Koike M, Yuasa Y (2004) Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol 24(2):257–263

    PubMed  CAS  Google Scholar 

  11. Jaenisch R, Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132(4):567–582

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Sherwood RI, Chen TY, Melton DA (2009) Transcriptional dynamics of endodermal organ formation. Dev Dyn 238(1):29–42

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Gao N, White P, Kaestner KH (2009) Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell 16(4):588–599

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Raghoebir L, Bakker ER, Mills JC, Swagemakers S, Kempen MB, Munck AB, Driegen S, Meijer D, Grosveld F, Tibboel D, Smits R, Rottier RJ (2012) SOX2 redirects the developmental fate of the intestinal epithelium toward a premature gastric phenotype. J Mol Cell Biol 4(6):377–385

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Sanada Y, Yoshida K, Ohara M, Oeda M, Konishi K, Tsutani Y (2006) Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor SOX2: comparison of expression patterns between invasive components and cancerous or nonneoplastic intraductal components. Pancreas 32(2):164–170

    Article  PubMed  CAS  Google Scholar 

  16. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, Kim SY, Wardwell L, Tamayo P, Gat-Viks I, Ramos AH, Woo MS et al (2009) SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41(11):1238–1242

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi MJ, Hernandez-Garcia S, Elorriaga K, Pandiella A, Rezola R, Martin AG (2012) Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 31(11):1354–1365

    Article  PubMed  CAS  Google Scholar 

  18. Basu-Roy U, Seo E, Ramanathapuram L, Rapp TB, Perry JA, Orkin SH, Mansukhani A, Basilico C (2012) Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas. Oncogene 31(18):2270–2282

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Alonso MM, Diez-Valle R, Manterola L, Rubio A, Liu D, Cortes-Santiago N, Urquiza L, Jauregi P, Lopez de Munain A, Sampron N, Aramburu A, Tejada-Solis S et al (2011) Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS ONE 6(11):e26740

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. van Lier MG, Leenen CH, Wagner A, Ramsoekh D, Dubbink HJ, van den Ouweland AM, Westenend PJ, de Graaf EJ, Wolters LM, Vrijland WW, Kuipers EJ, van Leerdam ME et al (2012) Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome. J Pathol 226(5):764–774

    Article  PubMed  Google Scholar 

  21. Raghoebir L, Biermann K, Buscop-van Kempen M, Wijnen RM, Tibboel D, Smits R, Rottier RJ (2013) Disturbed balance between SOX2 and CDX2 in human vitelline duct anomalies and intestinal duplications. Virchows Arch 462(5):515–522

    Article  PubMed  CAS  Google Scholar 

  22. Ochieng JK, Schilders K, Kool H, Boerema-de Munck A, Buscop-van Kempen M, Gontan C, Smits R, Grosveld FG, Wijnen RM, Tibboel D, Rottier RJ (2014) Sox2 regulates the emergence of lung basal cells by directly activating the transcription of Trp63. Am J Respir Cell Mol Biol

  23. Arnold K, Sarkar A, Yram MA, Polo JM, Bronson R, Sengupta S, Seandel M, Geijsen N, Hochedlinger K (2011) Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9(4):317–329

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Maier S, Wilbertz T, Braun M, Scheble V, Reischl M, Mikut R, Menon R, Nikolov P, Petersen K, Beschorner C, Moch H, Kakies C et al (2011) SOX2 amplification is a common event in squamous cell carcinomas of different organ sites. Hum Pathol 42(8):1078–1088

    Article  PubMed  CAS  Google Scholar 

  25. Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, Rivers CS, Foo CK et al (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44(10):1111–1116

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Pham DL, Scheble V, Bareiss P, Fischer A, Beschorner C, Adam A, Bachmann C, Neubauer H, Boesmueller H, Kanz L, Wallwiener D, Fend F et al (2013) SOX2 expression and prognostic significance in ovarian carcinoma. Int J Gynecol Pathol 32(4):358–367

    Article  PubMed  CAS  Google Scholar 

  27. Comprehensive molecular characterization of human colon and rectal cancer (2012). Nature 487 (7407):330–337

  28. Neumann J, Bahr F, Horst D, Kriegl L, Engel J, Luque RM, Gerhard M, Kirchner T, Jung A (2011) SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer. BMC Cancer 11:518

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, Salto-Tellez M (2010) CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol 23(3):450–457

    Article  PubMed  CAS  Google Scholar 

  30. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M (2009) Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 16(12):3488–3498

    Article  PubMed  Google Scholar 

  31. Han X, Fang X, Lou X, Hua D, Ding W, Foltz G, Hood L, Yuan Y, Lin B (2012) Silencing SOX2 induced mesenchymal-epithelial transition and its expression predicts liver and lymph node metastasis of CRC patients. PLoS ONE 7(8):e41335

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by an Erasmus MC grant (LR).

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pediatric Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands

    Lalini Raghoebir, Marjon Buscop-van Kempen, Dick Tibboel & Robbert J. Rottier

  2. Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands

    Katharina Biermann, Hendrikus J. Dubbink, Winand N. M. Dinjens, Remko Hersmus & Leendert H. J. Looijenga

  3. Department of Gastroenterology and Hepatology, Erasmus Medical Centre, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

    Marco J. Bruno & Ron Smits

  4. Department of Cell Biology, Erasmus Medical Centre, Rotterdam, The Netherlands

    Robbert J. Rottier

Authors
  1. Lalini Raghoebir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katharina Biermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marjon Buscop-van Kempen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hendrikus J. Dubbink
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Winand N. M. Dinjens
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Remko Hersmus
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leendert H. J. Looijenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marco J. Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dick Tibboel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robbert J. Rottier
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ron Smits
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ron Smits.

Additional information

Ron Smits and Robbert J. Rottier contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Raghoebir, L., Biermann, K., Kempen, M.Bv. et al. Aberrant SOX2 expression in colorectal cancers does not correlate with mucinous differentiation and gastric mucin MUC5AC expression. Virchows Arch 465, 395–400 (2014). https://doi.org/10.1007/s00428-014-1638-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1638-y

Keywords

Search

Navigation