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Lennartsson, Johan
Publications (10 of 43) Show all publications
Heldin, C.-H., Lennartsson, J. & Westermark, B. (2018). Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. Journal of Internal Medicine, 283(1), 16-44
Open this publication in new window or tab >>Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 1, p. 16-44Article, review/survey (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.

Keyword
inhibitor, kinase, malignancy, receptor, signal transduction, PDGF
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-347709 (URN)10.1111/joim.12690 (DOI)000418411100002 ()28940884 (PubMedID)
Funder
Swedish Cancer Society, 2016/445; 2015/226; 2014/468Swedish Research Council, 2015-02757
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-04-06Bibliographically approved
Reyhani, V., Tsioumpekou, M., van Wieringen, T., Rask, L., Lennartsson, J. & Rubin, K. (2017). PDGF-BB enhances collagen gel contraction through a PI3K-PLCγ-PKC-cofilin pathway. Scientific Reports, 7(1), Article ID 8924.
Open this publication in new window or tab >>PDGF-BB enhances collagen gel contraction through a PI3K-PLCγ-PKC-cofilin pathway
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 8924Article in journal (Refereed) Published
Abstract [en]

Cell-mediated contraction of collagenous matrices is modulated by various growth factors and cytokines, such as platelet-derived growth factor-BB (PDGF-BB). Here we used a genetic cell model to delineate defined signaling pathways that enhance collagen gel contraction downstream of ligand-stimulated platelet-derived growth factor receptor-β (PDGF-Rβ). Our data show that PDGF BB-enhanced activations of phosphatidylinositol 3'-kinase (PI3K) and phospholipase Cγ (PLCγ) were necessary for PDGF-enhanced collagen gel contraction. Importantly, other defined signaling pathways down-stream of PDGF-Rβ were, however, dispensable. The decisive roles for PI3K and PLCγ were corroborated by experiments using selective inhibitors. Furthermore, we show that de-phosphorylation and thereby activation of cofilin that is important for the turnover of actin filaments, is depended on PI3K and PLCγ down-stream of PDGF-Rβ. Moreover, inhibition of protein kinase C (PKC) by GÖ6976 and bisindolylmaleimide-II abolished cofilin de-phosphorylation, as well as PDGF-enhanced contraction. In contrast, activation of the PKC protein family by 4β-phorbol 12-myristate 13-acetate (PMA) did not accelerate collagen gel contraction although it induced long-term cofilin de-phosphorylation, showing the need of a dynamic control of cofilin de-phosphorylation for PDGF-enhanced collagen gel contraction. Taken together, our data point to the involvement of a PI3K/PLCγ-PKC-cofilin pathway in both PDGF-enhanced cofilin de-phosphorylation and PDGF-enhanced collagen gel contraction.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-331647 (URN)10.1038/s41598-017-08411-1 (DOI)28827622 (PubMedID)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-20Bibliographically approved
Rorsman, C., Tsioumpekou, M., Heldin, C.-H. & Lennartsson, J. (2016). The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor beta (PDGFR beta) Internalization and Signaling. Journal of Biological Chemistry, 291(22), 11608-11618
Open this publication in new window or tab >>The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor beta (PDGFR beta) Internalization and Signaling
2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 22, p. 11608-11618Article in journal (Refereed) Published
Abstract [en]

Protein ubiquitination controls protein stability and subcellular localization of tyrosine kinase receptors, hence affecting signaling both quantitatively and qualitatively. In this report, we demonstrate that, after ligand stimulation, the PDGF beta receptor (PDGFR beta) becomes ubiquitinated in a manner requiring both the c-Cbl and Cbl-b ubiquitin ligases. Simultaneous depletion of c-Cbl and Cbl-b resulted in reduced ligand-induced PDGFR beta clearance from the cell surface because of reduced endocytosis of the receptor. Cbl-b formed a complex with c-Cbl, as well as with the PDGFR beta, in response to PDGF-BB stimulation. We were unable to find a direct interaction between the receptor and c-Cbl, raising the possibility that Cbl-b is necessary for c-Cbl to interact with PDGFR beta. Phosphorylated Tyr-1021 in PDGFR beta was the primary interaction site for Cbl-b, with some contribution from Tyr-1009. Depletion of c-Cbl and Cbl-b led to an increased ligand-induced tyrosine phosphorylation of the receptor. Several tyrosine residues with elevated phosphorylation (i.e. Tyr-579, Tyr-581, Tyr-1009, and Tyr-1021) have previously been shown to interact with Src kinases and PLC gamma. Indeed, in cells depleted of c-Cbl and Cbl-b, both Src and PLC gamma phosphorylation were enhanced, whereas activation of other pathways, such as Erk1/2 MAP kinase and Akt, were not affected. In addition, Stat3 phosphorylation, which has been connected to Src activity, was also elevated in cells lacking c-Cbl and Cbl-b. Functionally, we found that cells depleted of c-Cbl and Cbl-b were more prone to migrate toward PDGF-BB, whereas no reproducible effect on cell proliferation could be observed. In conclusion, internalization as well as signaling via PDGFR beta are controlled by ubiquitination.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-299504 (URN)10.1074/jbc.M115.705814 (DOI)000377264800013 ()27048651 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2017-11-28Bibliographically approved
Sooman, L., Freyhult, E., Jaiswal, A., Navani, S., Edqvist, P.-H., Pontén, F., . . . Ekman, S. (2015). FGF2 as a potential prognostic biomarker for proneural glioma patients. Acta Oncologica, 54(3), 385-394
Open this publication in new window or tab >>FGF2 as a potential prognostic biomarker for proneural glioma patients
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2015 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, p. 385-394Article in journal (Refereed) Published
Abstract [en]

Background. The survival of high-grade glioma patients is poor and the treatment of these patients can cause severe side effects. This fosters the necessity to identify prognostic biomarkers, in order to optimize treatment and diminish unnecessary suffering of patients. The aim of this study was to identify prognostic biomarkers for high-grade glioma patients.

Methods. Eleven proteins were selected for analysis due to their suggested importance for survival of patients with other types of cancers and due to a high variation in protein levels between glioma patients (according to the Human Protein Atlas, www.proteinatlas.org). Protein expression patterns of these 11 proteins were analyzed by immunohistochemistry in tumor samples from 97 high-grade glioma patients. The prognostic values of the proteins were analyzed with univariate and multivariate Cox regression analyses for the high-grade glioma patients, including subgroup analyses of histological subtypes and immunohistochemically defined molecular subtypes.

Results. The proteins with the most significant (univariate and multivariate p < 0.05) correlations were analyzed further with cross-validated Kaplan-Meier analyses for the possibility of predicting survival based on the protein expression pattern of the corresponding candidate. Random Forest classification with variable subset selection was used to analyze if a protein signature consisting of any combination of the 11 proteins could predict survival for the high-grade glioma patients and the subgroup with glioblastoma patients. The proteins which correlated most significantly (univariate and multivariate p < 0.05) to survival in the Cox regression analyses were Myc for all high-grade gliomas and FGF2, CA9 and CD44 for the subgroup of proneural gliomas, with FGF2 having a strong negative predictive value for survival. No prognostic signature of the proteins could be found.

Conclusion. FGF2 is a potential prognostic biomarker for proneural glioma patients, and warrants further investigation.

Keyword
Prognostic biomarkers, tissue microarray, immunohistochemistry, FGF2, CA9, CD44
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-214802 (URN)10.3109/0284186X.2014.951492 (DOI)000350646400012 ()25263081 (PubMedID)
Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2018-01-11Bibliographically approved
Vanlandewijck, M., Lebouvier, T., Mae, M. A., Nahar, K., Hornemann, S., Kenkel, D., . . . Betsholtz, C. (2015). Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification. PLoS ONE, 10(11), Article ID e0143407.
Open this publication in new window or tab >>Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143407Article in journal (Refereed) Published
Abstract [en]

Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-R beta. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-R beta autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLC. activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb(+/-); Pdgfrb(+/-) mice did not develop brain calcification, nor did Pdgfrb(redeye/redeye) mice, which show a 90% reduction of PDGFR beta protein levels. In contrast, Pdgfb(ret/ret) mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfb(ret/ret) mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfb(ret/ret) mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-R beta signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-272285 (URN)10.1371/journal.pone.0143407 (DOI)000365853900111 ()
Funder
EU, European Research CouncilSwedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg Foundation
Available from: 2016-01-15 Created: 2016-01-13 Last updated: 2017-11-30Bibliographically approved
Ma, H., Wardega, P., Mazaud, D., Klosowska-Wardega, A., Jurek, A., Engström, U., . . . Heldin, C.-H. (2015). Histidine-domain-containing protein tyrosine phosphatase regulates platelet-derived growth factor receptor intracellular sorting and degradation. Cellular Signalling, 27(11), 2209-2219
Open this publication in new window or tab >>Histidine-domain-containing protein tyrosine phosphatase regulates platelet-derived growth factor receptor intracellular sorting and degradation
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2015 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 27, no 11, p. 2209-2219Article in journal (Refereed) Published
Abstract [en]

Histidine domain-containing protein tyrosine phosphatase (HD-PTP) is a putative phosphatase that has been shown to affect the signaling and downregulation of certain receptor tyrosine kinases. To investigate if HD-PTP affects platelet-derived growth factor receptor beta (PDGFR beta) signaling, we employed the overexpression of HA-tagged HD-PTP, as well as siRNA-mediated and lentivirus shRNA-mediated silencing of HD-PTP in NIH3T3 cells. We found that HD-PTP was recruited to the PDGFR beta in a ligand-dependent manner. Depletion of HD-PTP resulted in an inability of PDGF-BB to promote tyrosine phosphorylation of the ubiquitin ligases c-Cbl and Cbl-b, with a concomitant missorting and reduction of the degradation of activated PDGFRS. In contrast, ligand-induced internalization of PDGFR beta was unaffected by HD-FTP silencing. Furthermore, the levels of STAM and Hrs of the ESCRT0 machinery were decreased, and immunofluorescence staining showed that in HD-PTP-depleted cells, PDGFR beta accumulated in large aberrant intracellular structures. After the reduction of HD-PTP expression, an NIH3T3-derived cell line that has autocrine PDGF-BB signaling (sis-3 T3) showed increased ability of anchorage-independent growth. However, exogenously added PDGF-BB promoted efficient additional colony formation in control cells, but was not able to do so in HD-PTP-depleted cells. Furthermore, cells depleted of HD-PTP migrated faster than control cells. In summary, HD-PTP affects the intracellular sorting of activated PDGFRS and the migration, proliferation and tumorigenicity of cells stimulated by PDGF.

Keyword
HD-PTP, PDGFR beta, STAT3, c-Cbl, Cbl-b, PLC gamma, ESCRT, Ubiquitination
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-264805 (URN)10.1016/j.cellsig.2015.07.020 (DOI)000361777500008 ()26232618 (PubMedID)
Funder
Swedish Cancer Society, 130519
Available from: 2015-11-02 Created: 2015-10-19 Last updated: 2017-12-01Bibliographically approved
Tsioumpekou, M., Papadopoulos, N., Burovic, F., Heldin, C.-H. & Lennartsson, J. (2015). Mechanism of platelet-derived growth factor (PDGF) Erk5 MAP-kinase activation is cell type-dependent and can be independent of PDGF receptor kinase activity. Paper presented at 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10, 2015. International Journal of Molecular Medicine, 36(Supplement: 1), S20-S20
Open this publication in new window or tab >>Mechanism of platelet-derived growth factor (PDGF) Erk5 MAP-kinase activation is cell type-dependent and can be independent of PDGF receptor kinase activity
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2015 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 36, no Supplement: 1, p. S20-S20Article in journal, Meeting abstract (Other academic) Published
National Category
Dentistry
Identifiers
urn:nbn:se:uu:diva-266290 (URN)000361863000064 ()
Conference
20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10, 2015
Available from: 2015-11-06 Created: 2015-11-06 Last updated: 2017-12-01Bibliographically approved
Strömberg, T., Feng, X., Delforoush, M., Berglund, M., Lin, Y., Axelson, M., . . . Enblad, G. (2015). Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells. Medical Oncology, 32(7), Article ID 188.
Open this publication in new window or tab >>Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells
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2015 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 7, article id 188Article in journal (Refereed) Published
Abstract [en]

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by inhibition of proliferation. Pretreatment of U-2932 or U-2940 cell lines with PPP at biologically active concentrations did not prevent ligand-induced phosphorylation of IGF-1R at Tyr1131/1136 or its downstream targets AKT and ERK1/2. In contrast, the IGF-1R inhibitor NVP-AEW541 clearly inhibited phosphorylation of IGF-1R and AKT, while ERK1/2 phosphorylation was less affected. Taken together, the inhibitory effects of PPP in DLBCL cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease. However, we suggest that the primary target of PPP in these cells is not related to inhibition of IGF-1R phosphorylation.

Keyword
Diffuse large B-cell lymphoma, DLBCL, Picropodophyllin, PPP, IGF-1R
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-256985 (URN)10.1007/s12032-015-0630-y (DOI)000355619300007 ()
Available from: 2015-07-01 Created: 2015-06-29 Last updated: 2017-12-04Bibliographically approved
Eger, G., Papadopoulos, N., Lennartsson, J. & Heldin, C.-H. (2014). NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar. PLoS ONE, 9(9), e109047
Open this publication in new window or tab >>NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e109047-Article in journal (Refereed) Published
Abstract [en]

The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-233387 (URN)10.1371/journal.pone.0109047 (DOI)000343671700217 ()25269081 (PubMedID)
Funder
Swedish Research Council, K2011-67X-21859-01-6Swedish Cancer Society, 130519
Available from: 2014-10-02 Created: 2014-10-02 Last updated: 2017-12-05Bibliographically approved
Sooman, L., Ekman, S., Tsakonas, G., Jaiswal, A., Navani, S., Edqvist, P.-H., . . . Lennartsson, J. (2014). PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas. Tumor Biology, 35(5), 4479-4488
Open this publication in new window or tab >>PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas
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2014 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 5, p. 4479-4488Article in journal (Refereed) 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.

Keyword
high-grade glioma, PTPN6, SHP1, survival, chemotherapy, methylation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-214761 (URN)10.1007/s13277-013-1590-5 (DOI)000335759800063 ()
Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2018-01-11Bibliographically approved
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