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PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
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2014 (Engelska)Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, nr 5, s. 4479-4488Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: The prognosis of high-grade glioma patients is poor and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase, non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients and the epigenetic regulation of the expression of PTPN6 and the role of its expression in chemotherapy resistance in glioma-derived cells.

Material and methods: PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6 overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite-Pyrosequencing and demethylation of PTPN6 was done with decitabine treatment.

Results: PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p=0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increased resistance (p<0.05) to the chemotherapeutic drugs bortezomib, cisplatin and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis or autophagy. Low PTPN6 promoter methylation correlated to protein expression and the protein expression was increased upon demethylation in glioma-derived cells.

Conclusion: PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients and in glioma-derived cells its expression is epigenetically regulated and influences the response to chemotherapy.

Ort, förlag, år, upplaga, sidor
2014. Vol. 35, nr 5, s. 4479-4488
Nyckelord [en]
high-grade glioma, PTPN6, SHP1, survival, chemotherapy, methylation
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-214761DOI: 10.1007/s13277-013-1590-5ISI: 000335759800063OAI: oai:DiVA.org:uu-214761DiVA, id: diva2:685632
Tillgänglig från: 2014-01-09 Skapad: 2014-01-09 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Ingår i avhandling
1. Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
Öppna denna publikation i ny flik eller fönster >>Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The survival for high-grade glioma patients is poor and the treatment may cause severe side effects. A common obstacle in the treatment is chemoresistance. To improve the quality of life and prolong survival for these patients prognostic biomarkers and new approaches for chemotherapy are needed. To this end, a strategy to evade chemoresistance was evaluated by combining chemotherapeutic drugs with agents inhibiting resistance mechanisms identified by a bioinformatic analysis (paper I). The prognostic value of 13 different proteins was analyzed in this thesis (papers II-IV). Two of them, p38 mitogen-activated protein kinase (MAPK) and protein tyrosine phosphatase non-receptor type 6 (PTPN6, also known as SHP1) were analyzed for their potential as targets in combination chemotherapy (in paper III and IV, respectively).

 

We found that:

  1. PTPN6 expression and methylation status may be important for survival of anaplastic glioma patients, p38 MAPK phosphorylation may be a potential negative prognostic biomarker for high-grade glioma patients and FGF2 expression may be a potential negative prognostic biomarker for proneural glioma patients.
  2. PTPN6 may be a useful target for combination chemotherapy with cisplatin, melphalan or bortezomib in high-grade gliomas. The following drug combinations; camptothecin combined with an EGFR or RAC1 inhibitor, imatinib combined with a Notch or RAC1 inhibitor, temozolomide combined with an EGFR or FAK inhibitor and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for high-grade gliomas.
Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 74
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 965
Nyckelord
High-grade glioma, prognostic biomarkers, combination chemotherapy, DNA methylation, FGF2, p38 MAPK, PTPN6, camptothecin, imatinib, vandetanib, EGFR, RAC1, Notch
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi
Forskningsämne
Medicinsk vetenskap; Onkologi
Identifikatorer
urn:nbn:se:uu:diva-215079 (URN)978-91-554-8839-0 (ISBN)
Disputation
2014-03-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-02-13 Skapad: 2014-01-10 Senast uppdaterad: 2018-01-11

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Sooman, LindaEkman, SimonTsakonas, GeorgiosEdqvist, Per-HenrikPontén, FredrikBergström, StefanBlomquist, ErikBergqvist, MichaelGullbo, JoachimLennartsson, Johan

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Sooman, LindaEkman, SimonTsakonas, GeorgiosEdqvist, Per-HenrikPontén, FredrikBergström, StefanBlomquist, ErikBergqvist, MichaelGullbo, JoachimLennartsson, Johan
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Enheten för onkologiMolekylär och morfologisk patologiScience for Life Laboratory, SciLifeLabCancerfarmakologi och beräkningsmedicinLudwiginstitutet för cancerforskning
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