Expressionsanalyse für die tumorassoziierten Gene IL13Rα2, OLIG2 und DBCCR1 in diffusen und anaplastischen Astrozytomen, sowie Glioblastomen und deren Rezidiven
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Philipps-Universität Marburg
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Abstract
Objective:
Due to their limited therapy options and comparatively poor clinical prognosis the type and timing of appearance of genetic alterations in the course of oncogenesis of astocytic tumors is of great scientific interest. In this thesis an expression analysis of the tumor-associated genes IL13Rα2, OLIG2 and DBCCR1 was performed on diffuse and anaplastic astrocytomas as well as on glioblastomas and recurrent glioblastomas.
IL13Rα2 encodes for a 65 kDa protein which forms one of the possible subunits of the interleukin-13 receptor and is highly expressed on various kinds of human tumor cells. One of the functions of the IL13Rα2 chain is the one of a blind-receptor for interleukin-4. Since the interaction of IL-4 with its regular receptor has a negative effect on cell-proliferation, a high IL13Rα2 expression causes a reduction of this effect. In addition IL13Rα2 binds IL-13 with a very high affinity which makes it a target-structure for a specific chemotherapy with a fusion-protein consisting of IL-13 and a pseudomonas exotoxin.
The gene OLIG2 encodes for a basic helix-loop-helix transcription-factor which has an important function during the differentiation of motoneurons as well as oligodendrocytes and astrocytes from the neuronal progenitor cells. OLIG2 inhibits the complex formation between the transcription-coactivator p300 and STAT3. This leads to a reduced GFAP expression, since GFAP is an important promoter of astrocyte differentiation a high OLIG2 expression has a negative effect on astrocyte proliferation.
DBCCR1 has a proposed function as a tumorsuppressor gene. Especially in bladder cancer a deletion or functional inactivation of this gene has been observed. DBCCR1 seems to affect the cell cycle. Re-inducing the expression of this gene for example in bladder-cancer cells has lead to an accumulation of cells in the G1-phase of the cell cycle and a reduction of cells in the S- and G2/M-phase.
Material and Methods:
Research was conducted on a total of 51 native tumor-samples, 6 of them were diffuse astrocytomas, 11 were anaplastic astocytomas, 23 were primary glioblastomas and 11 were recurrent glioblastomas after previous resection and treatment with radiation (60 Gy) and chemotherapy with Nimustine (ACNU) and Teniposid (VM26). A relative quantification of the mRNA expression was performed by real-time PCR analysis using the ABI™ PRISM 7700 and Qiagen QuantiTect© SYBR Green PCR kits. Statistical significance of differences in the expression levels between the different tumor grades was evaluated using the independent samples T-test.
Results:
Statistical evaluation of the collected data showed a significantly reduced IL13Rα2 expression in recurrent glioblastomas compared with untreated primary glioblastomas. The combined data of the untreated anaplastic astrocytomas and primary glioblastomas showed a significant difference in expression compared to the recurrent glioblastomas as well.
OLIG2 expression in anaplastic astrocytomas was significantly higher than in all other tumor-grades, but the comparison of the other groups showed no significant differences.
The results for the DBCCR1 expression in the different tumor-grades did not reveal any statistically relevant differences.
Conclusion:
The results of this thesis do not point towards an involvement of IL13Rα2 in the malignant progress from diffuse astrocytomas to glioblastomas. But the significantly reduced expression of IL13Rα2 in recurrent glioblastomas after combined radiation and chemotherapy imply a possible contribution of this gene to the formation of recurrent tumors. In this case IL13Rα2 could serve as a protective factor against tumor-specific therapy and / or lead to higher proliferation-rate of the malignant cells.
The significantly higher OLIG2 expression in anaplastic astrocytomas compared to all other tumor-grades supports the histomorphological heterogeneity of these malignomas. On the other hand the expression-level of OLIG2 could possibly serve as a prognostic marker for the expectable clinical success of chemotherapy. As a gene involved into differentiation processes OLIG2 can be found especially in oligodendrocytes. Since oligodendroglioma in general show a better response to chemotherapy than other gliomas, it is possible that anaplastic astrocytes with a high OLIG2 expression show a better reaction to this kind of therapy as well.
The absence of statistically significant differences between the DBCCR1 expression in the examined tumor-samples points towards a missing function of this gene in the oncogenisis of astrocytic tumors in contrast to its role in bladder-cancer.
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Dates
Created: 2011Issued: 2011-06-28Updated: 2011-08-08
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
IL13Rα2DBCCR1glioblastomaOLIG2messenger-RNAsemiquantitative real-time pcrastrocytoma
DFG-subjects
Messenger-RNSGlioblastomAstrozytom
DDC-Numbers
610
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Kalk, Jens-Martin: Expressionsanalyse für die tumorassoziierten Gene IL13Rα2, OLIG2 und DBCCR1 in diffusen und anaplastischen Astrozytomen, sowie Glioblastomen und deren Rezidiven. : Philipps-Universität Marburg 2011-06-28. DOI: https://doi.org/10.17192/z2011.0421.
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This item has been published with the following license: In Copyright