Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Senanayake, U.
Molecular markers to characterise nephroblastoma and stage2 colorectal carcinoma
[ Dissertation ] Medical University of Graz; 2012. pp. 132
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- Autor*innen der Med Uni Graz:
- Senanayake Upeka
- Betreuer*innen:
- Höfler Gerald
- Speicher Michael
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- Abstract:
- Nephroblastoma and colorectal carcinoma (CC) are two tumour entities that occur in children and adults, respectively. Nephroblastomas are embryonal neoplasms that histologically and ultrastructurally recapitulate developing kidney. CC is one of the leading causes of cancer deaths worldwide and treatment is determined according to clinic-pathological staging system. Herein, we have analysed different molecular markers by a variety of techniques to characterise nephroblastoma and stage2 CC. SIX2 is one of the characteristic genetic factors, which maintains renal progenitor cells in foetal kidney. Blastema showed a significantly higher level of mRNA expression of SIX2 compared to epithelial regions regardless of the subtype of nephroblastoma and a strong nuclear expression was detected in blastema. Upstream activators of SIX2 indicated that the signal transduction pathway was activated in most, but not all nephroblastomas. Increased percentage of cells in the S-phase and cellular migration was identified in cells overexpressing SIX2. Kidney enriched miRNAs; miR-192, miR-215 and miR-194 had a significantly lower expression in nephroblastomas regardless of the subtype compared to mature kidney. Kidney parenchyma had a significantly higher expression of miR-192, miR-194, miR-215 and miR-200c compared to nephrogenic rests (NRs). Activin receptor type 2B (ACVR2B), a member of the TGF-ß pathway, was identified as single common target gene for miR-192, miR-215, miR-194, miR-141 and miR-200c in-silico. The interaction between miRNAs and ACVR2B was also verified by an in-vitro assay. A distinct mRNA and protein expression of ACVR2B was detected in nephroblastomas. Array CGH analysis revealed amplifications of HOXC6 in nephroblastomas and NRs. MRNA expression of HOXC6 V1 and V2 was concordant with HOXC6 amplifications. Overexpressing V1 and V2 in a nephroblastoma cell line identified distinct up or down regulation of target genes by V1 compared to V2. Different molecular and immunohistochemical markers were analysed in a small cohort of stage2 CC patients. Mutations in PIK3CA exon 9 had a significant impact on disease free survival. In conclusion, SIX2, based on a differential regulation of ACVR2B by miRNAs and HOXC6 V1, V2 appears to be an important molecular marker in the pathogenesis of nephroblastomas. Mutations in PIK3CA exon 9 are useful prognostic markers in stage2 CC.