Advertisement

Tumor Biology

, Volume 36, Issue 11, pp 9023–9030 | Cite as

Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer

  • L. Oliveira-Ferrer
  • A. Heßling
  • F. Trillsch
  • S. Mahner
  • K. Milde-Langosch
Research Article

Abstract

Ovarian cancer (OvCa) accounts for the highest tumor-related mortality among gynecological malignancies, but the underlying mechanisms are poorly understood. Glycosaminoglycans are abundantly present in ovarian tumors, and there is rising evidence that chondroitin sulfate (CS) as well as diverse carbohydrate sulfotransferases (CHSTs), the enzymes involved in the sulfation process of these structures, plays an important role in metastatic spread of tumor cells. mRNA expression levels of CHST3/7/11/12/13/15 were compared between malignant (86 OvCas) and non-malignant tumors (6 borderline tumors and 3 cystadenomas). CHST11 and CHST15 were further chosen for Western blot analysis in a cohort of 216 OvCas. Protein expression levels were correlated with clinicopathologic prognostic parameters and survival data. A significantly higher mRNA expression of CHST11, CHST12, and CHST15 was measured in ovarian cancer samples in comparison to non-malignant ones, and the same trend was observed for CHST13. For CHST3 and CHST7, no significant differences were found between the two groups. At protein level, high CHST11 expression was independently associated with unfavorable progression-free survival (PFS; p = 0.027). A similar trend was observed for CHST15, showing a nearly significant correlation between high expression levels and shorter recurrence-free survival in patients without macroscopic residual tumor after surgery (p = 0.053). We conclude that CHSTs involved in the synthesis of CS-A and CS-E might influence ovarian cancer progression, and we suggest CHST11 as independent unfavorable prognostic factor in this entity.

Keywords

Ovarian cancer Prognostic factors Chondroitin CHST11 

Notes

Acknowledgments

We are very grateful to the excellent technical assistance of Maila Rossberg and Kathrin Eylmann.

Supplementary material

13277_2015_3652_MOESM1_ESM.xlsx (11 kb)
ESM 1 (XLSX 10 kb)

References

  1. 1.
    Arend RC, Londono-Joshi AI, Straughn Jr JM, Buchsbaum DJ. The Wnt/beta-catenin pathway in ovarian cancer: a review. Gynecol Oncol. 2013;131:772–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Asimakopoulou AP, Theocharis AD, Tzanakakis GN, Karamanos NK. The biological role of chondroitin sulfate in cancer and chondroitin-based anticancer agents. In Vivo. 2008;22:385–9.PubMedGoogle Scholar
  3. 3.
    Catterall JB, Jones LM, Turner GA. Membrane protein glycosylation and CD44 content in the adhesion of human ovarian cancer cells to hyaluronan. Clin Exp Meta. 1999;17:583–91.CrossRefGoogle Scholar
  4. 4.
    Cooney CA, Jousheghany F, Yao-Borengasser A, Phanavanh B, Gomes T, Kieber-Emmons AM, et al. Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells. Breast Cancer Res BCR. 2011;13:R58.CrossRefPubMedGoogle Scholar
  5. 5.
    Eckhoff K, Flurschutz R, Trillsch F, Mahner S, Janicke F, Milde-Langosch K. The prognostic significance of Jun transcription factors in ovarian cancer. J Cancer Res Clin Oncol. 2013;139:1673–80.CrossRefPubMedGoogle Scholar
  6. 6.
    Evers MR, Xia G, Kang HG, Schachner M, Baenziger JU. Molecular cloning and characterization of a dermatan-specific N-acetylgalactosamine 4-O-sulfotransferase. J Biol Chem. 2001;276:36344–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Gardner MJ, Jones LM, Catterall JB, Turner GA. Expression of cell adhesion molecules on ovarian tumour cell lines and mesothelial cells, in relation to ovarian cancer metastasis. Cancer Lett. 1995;91:229–34.CrossRefPubMedGoogle Scholar
  8. 8.
    Hemmerich S, Rosen SD. Carbohydrate sulfotransferases in lymphocyte homing. Glycobiology. 2000;10:849–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Hiraoka N, Nakagawa H, Ong E, Akama TO, Fukuda MN, Fukuda M. Molecular cloning and expression of two distinct human chondroitin 4-O-sulfotransferases that belong to the HNK-1 sulfotransferase gene family. J Biol Chem. 2000;275:20188–96.CrossRefPubMedGoogle Scholar
  10. 10.
    Iida J, Dorchak J, Clancy R, Slavik J, Ellsworth R, Katagiri Y, et al. Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth. Exp Cell Res. 2015;330:358–70.CrossRefPubMedGoogle Scholar
  11. 11.
    Iida J, Meijne AM, Oegema Jr TR, Yednock TA, Kovach NL, Furcht LT, et al. A role of chondroitin sulfate glycosaminoglycan binding site in alpha4beta1 integrin-mediated melanoma cell adhesion. J Biol Chem. 1998;273:5955–62.CrossRefPubMedGoogle Scholar
  12. 12.
    Iida J, Wilhelmson KL, Ng J, Lee P, Morrison C, Tam E, et al. Cell surface chondroitin sulfate glycosaminoglycan in melanoma: role in the activation of pro-MMP-2 (pro-gelatinase A). Biochem J. 2007;403:553–63.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Joo EJ, Weyers A, Li G, Gasimli L, Li L, Choi WJ, et al. Carbohydrate-containing molecules as potential biomarkers in colon cancer. Om J Integr Biol. 2014;18:231–41.CrossRefGoogle Scholar
  14. 14.
    Kang HG, Evers MR, Xia G, Baenziger JU, Schachner M. Molecular cloning and expression of an N-acetylgalactosamine-4-O-sulfotransferase that transfers sulfate to terminal and non-terminal beta 1,4-linked N-acetylgalactosamine. J Biol Chem. 2001;276:10861–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Kang HG, Evers MR, Xia G, Baenziger JU, Schachner M. Molecular cloning and characterization of chondroitin-4-O-sulfotransferase-3. A novel member of the HNK-1 family of sulfotransferases. J Biol Chem. 2002;277:34766–72.CrossRefPubMedGoogle Scholar
  16. 16.
    Kawashima H, Atarashi K, Hirose M, Hirose J, Yamada S, Sugahara K, et al. Oversulfated chondroitin/dermatan sulfates containing GlcAbeta1/IdoAalpha1-3GalNAc(4,6-O-disulfate) interact with L- and P-selectin and chemokines. J Biol Chem. 2002;277:12921–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AH, Miyasaka M. Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J Biol Chem. 2000;275:35448–56.CrossRefPubMedGoogle Scholar
  18. 18.
    Kitagawa H, Fujita M, Ito N, Sugahara K. Molecular cloning and expression of a novel chondroitin 6-O-sulfotransferase. J Biol Chem. 2000;275:21075–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Mahner S, Baasch C, Schwarz J, Hein S, Wolber L, Janicke F, Milde-Langosch K. C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. BritishGoogle Scholar
  20. 20.
    Martinez P, Vergoten G, Colomb F, Bobowski M, Steenackers A, Carpentier M, et al. Over-sulfated glycosaminoglycans are alternative selectin ligands: insights into molecular interactions and possible role in breast cancer metastasis. Clin Exp Meta. 2013;30:919–31.CrossRefGoogle Scholar
  21. 21.
    Mikami T, Mizumoto S, Kago N, Kitagawa H, Sugahara K. Specificities of three distinct human chondroitin/dermatan N-acetylgalactosamine 4-O-sulfotransferases demonstrated using partially desulfated dermatan sulfate as an acceptor: implication of differential roles in dermatan sulfate biosynthesis. J Biol Chem. 2003;278:36115–27.CrossRefPubMedGoogle Scholar
  22. 22.
    Monzavi-Karbassi B, Stanley JS, Hennings L, Jousheghany F, Artaud C, Shaaf S, et al. Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines9. Int J Cancer J Int Cancer. 2007;120:1179–91.CrossRefGoogle Scholar
  23. 23.
    Nakayama F, Umeda S, Ichimiya T, Kamiyama S, Hazawa M, Yasuda T, et al. Sulfation of keratan sulfate proteoglycan reduces radiation-induced apoptosis in human Burkitt’s lymphoma cell lines. FEBS Lett. 2013;587:231–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Oliveira-Ferrer L, Rossler K, Haustein V, Schroder C, Wicklein D, Maltseva D, et al. c-FOS suppresses ovarian cancer progression by changing adhesion. Br J Cancer. 2014;110:753–63.CrossRefPubMedGoogle Scholar
  25. 25.
    Prinz RD, Willis CM, Viloria-Petit A, Kluppel M. Elimination of breast tumor-associated chondroitin sulfate promotes metastasis. Genet Mol Res GMR. 2011;10:3901–13.CrossRefPubMedGoogle Scholar
  26. 26.
    Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, et al. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem. 2004;279:9190–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Shworak NW, Liu J, Petros LM, Zhang L, Kobayashi M, Copeland NG, et al. Multiple isoforms of heparan sulfate D-glucosaminyl 3-O-sulfotransferase. Isolation, characterization, and expression of human cdnas and identification of distinct genomic loci. J Biol Chem. 1999;274:5170–84.CrossRefPubMedGoogle Scholar
  28. 28.
    Strobel T, Cannistra SA. Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro. Gynecol Oncol. 1999;73:362–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Takeuchi J. Effect of chondroitinases on the growth of solid Ehrlich ascites tumour. BritishGoogle Scholar
  30. 30.
    Vallen MJ, Schmidt S, Oosterhof A, Bulten J, Massuger LF, van Kuppevelt TH. Primary ovarian carcinomas and abdominal metastasis contain 4,6-disulfated chondroitin sulfate rich regions, which provide adhesive properties to tumour cells. PLoS One. 2014;9:e111806.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang X, Wang Y, Yu L, Sakakura K, Visus C, Schwab JH, et al. CSPG4 in cancer: multiple roles. Curr Mol Med. 2010;10:419–29.CrossRefPubMedGoogle Scholar
  32. 32.
    Willis CM, Kluppel M. Inhibition by chondroitin sulfate E can specify functional Wnt/beta-catenin signaling thresholds in NIH3T3 fibroblasts. J Biol Chem. 2012;287:37042–56.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Willis CM, Kluppel M. Chondroitin sulfate-E is a negative regulator of a pro-tumorigenic Wnt/beta-catenin-collagen 1 axis in breast cancer cells. PLoS One. 2014;9:e103966.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yamada S, Sugahara K. Potential therapeutic application of chondroitin sulfate/dermatan sulfate. Curr Drug Discov Technol. 2008;5:289–301.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • L. Oliveira-Ferrer
    • 1
  • A. Heßling
    • 1
  • F. Trillsch
    • 1
  • S. Mahner
    • 1
  • K. Milde-Langosch
    • 1
  1. 1.Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany

Personalised recommendations