Skip to main content

Advertisement

SpringerLink
Log in

Expression and clinical role of the dipeptidyl peptidases DPP8 and DPP9 in ovarian carcinoma

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

Abstract

Dipeptidyl peptidase 9 (DPP9) was recently identified as fusion gene in ovarian high-grade serous carcinoma (HGSC). The aim of this study was to analyze the expression and clinical relevance of DPP8 and DPP9 in ovarian carcinoma, with focus on HGSC. mRNA expression by qRT-PCR of DPP8 and DPP9 was analyzed in 232 carcinomas, including 114 effusions and 118 surgical specimens (89 ovarian, 29 solid metastases). DPP8 and DPP9 protein expression was analyzed in 92 effusions. DPP8 and DPP9 mRNA was overexpressed in effusions compared to solid lesions in analysis of all histotypes (p < 0.001 both), as well as in analysis limited to HGSC (p < 0.001 for DPP9, p = 0.002 for DPP8). DPP9 mRNA was additionally overexpressed in HGSC compared to other histotypes (p = 0.021). DPP8 and DPP9 protein was expressed in carcinoma cells in 31/92 (37%) and 81/92 (88%) effusions, respectively. DPP8 protein expression in HGSC effusions was significantly related to better (complete) chemoresponse at diagnosis (p = 0.005). DPP8 and DPP9 mRNA and protein expression was unrelated to survival in analysis of the entire effusion cohort. However, higher DPP9 mRNA levels were significantly related to longer overall survival in pre-chemotherapy effusions (p = 0.049). In conclusion, DPP8 and DPP9 mRNA is frequently expressed in ovarian carcinoma, whereas DPP9 is more frequently expressed at the protein level. DPP8 and DPP9 may be related to less aggressive disease in advanced-stage HGSC.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Reid BM, Permuth JB, Sellers TA (2017) Epidemiology of ovarian cancer: a review. Cancer Biol Med 14:9–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics. CA Cancer J Clin 68:284–296. https://doi.org/10.3322/caac.21456

    Article  PubMed  PubMed Central  Google Scholar 

  3. Davidson B (2018) Ovarian carcinoma. In: Davidson B, Firat P, Michael CW (eds) Serous effusions - etiology, diagnosis, prognosis and therapy, 2nd edn. Springer, London

    Google Scholar 

  4. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (2014) WHO classification of tumors of female reproductive organs. IARC, Lyon

    Google Scholar 

  5. Davidson B (2016) Recently identified drug resistance biomarkers in ovarian cancer. Expert Rev Mol Diagn 16:569–578

    Article  CAS  PubMed  Google Scholar 

  6. Pitman MR, Sulda ML, Kuss B, Abbott CA (2009) Dipeptidyl peptidase 8 and 9--guilty by association? Front Biosci (Landmark Ed) 14:3619–3633

    Article  CAS  Google Scholar 

  7. Zhang H, Chen Y, Keane FM, Gorrell MD (2013) Advances in understanding the expression and function of dipeptidyl peptidase 8 and 9. Mol Cancer Res 11:1487–1496

    Article  CAS  PubMed  Google Scholar 

  8. Zhang H, Maqsudi S, Rainczuk A, Duffield N, Lawrence J, Keane FM, Justa-Schuch D, Geiss-Friedlander R, Gorrell MD, Stephens AN (2015) Identification of novel dipeptidyl peptidase 9 substrates by two-dimensional differential in-gel electrophoresis. FEBS J 282:3737–3757

    Article  CAS  PubMed  Google Scholar 

  9. Smebye ML, Agostini A, Johannessen B, Thorsen J, Davidson B, Tropé CG, Heim S, Skotheim RI, Micci F (2017) Involvement of DPP9 in gene fusions in serous ovarian carcinoma. BMC Cancer 17:642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hoogstraat M, de Pagter MS, Cirkel GA, van Roosmalen MJ, Harkins TT, Duran K, Kreeftmeijer J, Renkens I, Witteveen PO, Lee CC, Nijman IJ, Guy T, van 't Slot R, Jonges TN, Lolkema MP, Koudijs MJ, Zweemer RP, Voest EE, Cuppen E, Kloosterman WP (2014) Genomic and transcriptomic plasticity in treatment-naive ovarian cancer. Genome Res 24:200–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fu J, Bian L, Zhao L, Dong Z, Gao X, Luan H, Sun Y, Song H (2010) Identification of genes for normalization of quantitative real-time PCR data in ovarian tissues. Acta Biochim Biophys Sin Shanghai 42:568–574

    Article  CAS  PubMed  Google Scholar 

  12. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  13. Wilson CH, Abbott CA (2012) Expression profiling of dipeptidyl peptidase 8 and 9 in breast and ovarian carcinoma cell lines. Int J Oncol 41:919–932

    Article  CAS  PubMed  Google Scholar 

  14. Yao TW, Kim WS, Yu DM, Sharbeen G, McCaughan GW, Choi KY, Xia P, Gorrell MD (2011) A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling. Mol Cancer Res 9:948–959

    Article  CAS  PubMed  Google Scholar 

  15. Tang Z, Li J, Shen Q, Feng J, Liu H, Wang W, Xu L, Shi G, Ye X, Ge M, Zhou X, Ni S (2017) Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non-small cell lung cancer (NSCLC). Int J Cancer 140:1620–1632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kajiyama H, Kikkawa F, Khin E, Shibata K, Ino K, Mizutani S (2003) Dipeptidyl peptidase IV overexpression induces up-regulation of E-cadherin and tissue inhibitors of matrix metalloproteinases, resulting in decreased invasive potential in ovarian carcinoma cells. Cancer Res 63:2278–2283

    CAS  PubMed  Google Scholar 

  17. Kajiyama H, Shibata K, Ino K, Mizutani S, Nawa A, Kikkawa F (2010) The expression of dipeptidyl peptidase IV (DPPIV/CD26) is associated with enhanced chemosensitivity to paclitaxel in epithelial ovarian carcinoma cells. Cancer Sci 101:347–354

    Article  CAS  PubMed  Google Scholar 

  18. Mhawech-Fauceglia P, Yan L, Sharifian M, Ren X, Liu S, Kim G, Gayther SA, Pejovic T, Lawrenson K (2015) Stromal expression of fibroblast activation protein alpha (FAP) predicts platinum resistance and shorter recurrence in patients with epithelial ovarian cancer. Cancer Microenviron 8:23–31

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by The Inger and John Fredriksen Foundation for Ovarian Cancer Research. Marta Brunetti is supported by a grant from the South-East Health Region of Norway.

Author information

Authors and Affiliations

  1. Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310, Oslo, Norway

    Marta Brunetti, Arild Holth & Ben Davidson

  2. Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway

    Marta Brunetti, Ioannis Panagopoulos & Francesca Micci

  3. Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, N-0316, Oslo, Norway

    Marta Brunetti, Anne Cathrine Staff & Ben Davidson

  4. Division of Obstetrics and Gynecology, Ullevål University Hospital, N-0407, Oslo, Norway

    Anne Cathrine Staff

Authors
  1. Marta Brunetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arild Holth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ioannis Panagopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Cathrine Staff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesca Micci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ben Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MB performed the PCR experiments and wrote the manuscript.

AH performed the IHC experiments.

IP participated in performing the PCR experiments and critically read the manuscript.

ACS provided clinical data and specimens and critically read the manuscript.

FM designed the study, supervised the PCR experiments, and critically read the manuscript.

BD designed the study, performed the statistical analysis, scored the immunostains, and supervised the writing of the manuscript.

Corresponding author

Correspondence to Ben Davidson.

Ethics declarations

The study was approved by the Regional Committee for Medical Research Ethics in Norway.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brunetti, M., Holth, A., Panagopoulos, I. et al. Expression and clinical role of the dipeptidyl peptidases DPP8 and DPP9 in ovarian carcinoma. Virchows Arch 474, 177–185 (2019). https://doi.org/10.1007/s00428-018-2487-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-018-2487-x

Keywords

Search

Navigation