Expressionsunterschiede von Wif1 und Rab34 bei Gliomen

Onkologische Reaktionswege, bei denen unter anderem die Wnt-Protein-Familie und die Ras-Gene eine bedeutende Rolle spielen, stehen im Interesse der derzeitigen medizinischen Forschung. Sowohl das Gen Wif1 als auch Rab34 könnten möglicherweise auch als wichtige Schaltpunkte innerhalb der Gliomgenes...

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Bibliographic Details
Main Author: Henzgen, Julia
Contributors: Bertalanffy, H. (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2009
Operative Medizin
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Table of Contents: Major oncologic pathways, such as the Wnt protein family and the Ras genes belong to oncogenes that play a significant role in tumor genesis pathways. Wif1 and Rab34 have been implicated to be involved in glioma genesis. Wif1 is a secreted antagonist of Wnt signalling and functions by direct binding to Wnt ligands in the extracellular space. There is evidence that intracellular downregulation of β-catenin correlates with reduced expression of oncogenes. On the other hand down-regulation of Wif1 results in a higher expression level of Wnt, which causes higher transcription activity through the β-catenin pathway. Rab34 belongs to the group of Ras genes and is involved in various steps along the exocytic and endocytic pathways. By changing between the active and inactive form, Rab-proteins are considered key regulatory factors for membrane traffic. This biological activity causes vesicular formation, movement of organelles and membrane traffic by recruitment of effector proteins. Previous microarray analysis showed a significant incidence of different gene expressions of Rab34 and Wif1 in astrocytomas of WHO-grade III and glioblastomas. The current study analysed the incidence of Wif1 and Rab34 expression in a larger number of tissue samples from astrocytomas of WHO-grades II, III, glioblastomas and first-time recurrent glioblastomas. Last-mentioned were treated by radiation and chemo-therapy. To study possible differences in their expression, semiquantitative two-step RT Real-Time PCR examinations on a total of 51 tissue samples of astrocytomas WHOgrade II, III, glioblastomas and first-time recurrent glioblastomas were performed. Analysis were conducted using the ABI™ Sequence Detection System ABI PRISM® 7700 and Qiagen™ QuantiTect® SYBR® Green PCR Kits. According to the histological grading the arithmetic mean was calculated and compared by using the U-test. There is an immense uptake of Wif1 in astrocytomas from grade II to grade III. Strong reduction of Wif1 expression was present in glioblastomas compared to astrocytomas grade III. The expression level of astrocytomas grade II was nearly equivalent to the group of glioblastomas. Another up-regulation of Wif1-expression was seen in recurrent compared to primary glioblastomas. By using the U-test, there was a significant difference in expression level between astrocytomas grade III and recurrent glioblastomas as well as recurrent compared to primary glioblastomas. Rab34 showed the highest expression in astrocytomas grade III and displayed a strong reduction compared to the benign astrocytomas grade II. Moreover, Rab34- expression showed a down-regulation of astrocytomas grade III compared to primary glioblastomas. Expression level of Rab34 in glioblastomas showed a double increase from primary to recurrent glioblastomas. By using the U-test there was a significant difference in expression levels between recurrent when compared to primary glioblastomas. Both pathways may be operative in early glioma tumor genesis. Aberrant activation of the Wnt pathway indicates that loss of Wif1 expression may be an early event in tumor genesis as demonstrated by other groups for higher tumor stages like urinary bladder or prostate cancer. The data indicates that there is no correlation between tumorgrade and expression level of Wif1, but this probably demonstrates tissuespecific or tumor-specific expression. There is evidence for anti-apoptotic activity and potentiated malignity. Overexpression of Rab GTPases is detected in various kinds of cancer. The increasing expression of Rab34 in all glioma grades supports the previously suggested role of tumor genesis for astrocytomas. There is significant correlation between tumor stage and tumor-grade. Because of the uptake in expression level between recurrent when compared to primary glioblastomas, the Rab34 pathway might play an important role. On the basis of this result, membrane traffic in the axoplasma, microtubules- or actin-based motor complexes and regulation within the antigenic presentation may yield additional understanding.