Expression der pro-apoptotischen Apoptoseinhibitor-(IAP)Antagonisten XAF1, Smac/DIABLO und HtrA2 in Keimzelltumoren des Hodens

Zusammenfassung

Fragestellung: Eine verminderte Expression der IAP-Antagonisten XAF1, Smac/DIABLO und HtrA2 steht mit der Entwicklung und Progression diverser Tumorentitäten in Verbindung. Ziel dieser Studie war es, die mRNA-Expression dieser pro-apoptotischen Parameter in Keimzelltumoren des Hodens verglichen mit normalem Hodengewebe und eine mögliche Korrelation ihrer Expressionshöhe mit klinischen und pathologischen Charakteristika von Hodentumoren zu untersuchen. Material und Methoden: Die mRNA-Expression von XAF1, Smac/DIABLO und HtrA2 wurde mittels real-time RT-PCR in normalem Hodengewebe (n = 18), TIN-Proben (n = 4), Seminomen (n = 64) und Nichtseminomen (n = 35) quantifiziert. Ergebnisse: Verglichen mit normalen Hodenproben war die Expression von XAF1 in Keimzelltumoren erhöht (p < 0,001), wohingegen die von Smac/DIABLO und HtrA2 erniedrigt war (p < 0,001 und p < 0,001). Für Smac/DIABLO zeigte dabei ein signifikanter Trend in Richtung einer kontinuierlichen Abnahme der Expression von normalem Hodengewebe zu TIN-Proben und Seminomen und letztlich zu Nichtseminomen (p < 0,001). Des Weiteren stieg die Expression von XAF1 und HtrA2 mit Progression des klinischen Tumorstadiums bei Seminompatienten graduell an (p = 0,001 und p = 0,018), wobei die Expression beider Parameter eng korreliert war (Spearman rho Korrelationskoeffizient: 0,674; p < 0,001). Schlussfolgerung: Unsere Ergebnisse deuten auf eine Rolle der verminderten Expression von Smac/DIABLO und HtrA2 bei der Entwicklung und Progression von Keimzelltumoren des Hodens hin, wohingegen die Überexpression von XAF1 in diesen Tumoren möglicherweise zu ihrer außergewöhnlich guten Chemotherapiesensibilität beiträgt. In Anbetracht der zusätzlichen Korrelation der XAF1 und HtrA2 Expression mit dem klinischen Tumorstadium von Seminompatienten erscheint es sinnvoll, alle 3 IAP-Antagonisten als mögliche molekulare Parameter für die Vorhersage des Therapieansprechens und der Prognose von Keimzelltumorpatienten weiter zu evaluieren.

Abstract

Purpose: Down-regulation of the IAP antagonistis XAF1, Smac/DIABLO and HtrA2, has been related to the onset and progression of various malignancies. We examined the mRNA-expression of these pro-apoptotic parameters in testicular germ cell tumors (TGCT) and normal testicular tissue and correlated their expression levels to clinicopathological tumour features.Material and Methods: Real-time RT-PCR was used to quantify the mRNA-expression of XAF1, Smac/DIABLO and HtrA2 in normal testicular tissue (n = 18), carcinoma in situ (n = 4), seminomas (n = 64), and non-seminomatous germ cell tumors (n = 35). Results: Compared to normal testicular tissue, the expression levels of XAF1 were increased in TGCT (p < 0.001), whereas those of Smac/DIABLO and HtrA2 were decreased (p < 0.001 and p < 0.001). Smac/DIABLO expression levels showed a significant trend towards a gradual decrease from normal testicular tissue to CIS and seminomas and finally to NSGCT (p < 0.001). Moreover, XAF1 and HtrA2 expression levels gradually increased with progression of clinical tumour stage in seminoma patients (p = 0.001 and p = 0.018), their expression levels being strongly intercorrelated (Spearman rho correlation coefficient: 0.674; p < 0.001). Conclusion: These data suggest that a down-regulation of Smac/DIABLO and HtrA2 is implicated in the development and progression of TGCT, whereas overexpression of XAF1 in TGCT might contribute to their extraordinary sensitivity to chemotherapy. Regarding the additional correlation of XAF1 and HtrA2 expression with clinical tumour stage in seminoma patients, it appears reasonable to further evaluate these three IAP antagonists as molecular parameters for the prediction of treatment response and prognosis of TGCT patients.

XAF1 - HtrA2 - Smac/DIABLO - Keimzelltumor - Hoden - Apoptoseinhibitor

XAF1 - HtrA2 - Smac/DIABLO - testicular germ cell tumour - inhibitor of apoptosis

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