Bedeutung des Tumorsuppressors PTEN für das Nierenzellkarzinom

Zusammenfassung

Fragestellung: Das Tumorsuppressorgen PTEN (phosphatase and tensin homologue deleted from chromosome 10) kodiert für eine dual-spezifische Protein- und Phospholipid-Phosphatase, die regulatorisch in Zellproliferation, Apoptose und Zellmigration eingreift. Wir haben die Expression des PTEN-Proteins in der Tumorgenese des Nierenzellkarzinoms untersucht. Material und Methode: In 42 klarzelligen Nierenzellkarzinomen (NZK) und Onkozytomen sowie in dem gesunden Nierengewebe derselben Patienten wurde die Expression des PTEN-Proteins in Westernblot-Analysen untersucht. Die zelluläre Lokalisation von PTEN wurde immunhistochemisch analysiert. Ergebnisse: PTEN war in allen untersuchten gesunden Nierengewebeproben hoch exprimiert. Die immunhistochemischen Analysen zeigten, dass fast ausschließlich proximale Tubulus-Epithelzellen, die Vorläuferzellen der klarzelligen NZKs, PTEN-positiv waren. Innerhalb der proximalen Tubulus-Epithelzellen zeigte PTEN eine deutliche Assoziation mit der Zytoplasma-Membran. In klarzelligen NZKs war die PTEN-Expression, ermittelt im Westernblot, auf 10 % der Werte des gesunden Nierengewebes reduziert (p < 0,001). Diese Reduktion war bei Frauen drastischer als bei Männern (p = 0,006). Der Grad der Reduktion entsprach in hoch differenzierten (G1) Karzinomen dem in weniger differenzierten (G2 - G4) Karzinomen. Diese Beobachtung wurde durch die immunhistochemischen Studien bestätigt. Zudem zeigte sich, dass die Membran-Assoziation von PTEN in klarzelligen NZKs nicht mehr zu beobachten war. Im Gegensatz zu den PTEN-positiven proximalen Tubulus-Epithelzellen exprimierten die distalen Tubulus-Epithelzellen, aus denen sich die gutartigen Onkozytome entwickeln, PTEN nur sehr schwach. Verglichen mit den distalen Tubulus-Epithelzellen war keine Herunterregulation von PTEN in Onkozytomen zu beobachten. Schlussfolgerung: Während der frühen Karzinogenese des Nierenzellkarzinoms geht die PTEN-Expression und die Membran-Lokalisation von PTEN verloren, so dass PTEN als Tumormarker für das NZK herangezogen werden kann.

Abstract

Purpose: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a tumor suppressor gene that encodes a dual specific protein and phospholipid phosphatase. It affects cell proliferation, apoptosis and migration. In the present study we examined protein expression of PTEN in renal carcinogenesis. Materials and Methods: In 42 clear cell renal cell carcinomas (ccRCC) and oncocytomas as well as in the corresponding normal renal tissue of the same patients, PTEN protein levels were examined using Western blot analysis. Cellular localization was analysed by immunohistochemistry. Results: Western blot analysis showed a high expression of PTEN in all investigated normal renal tissue specimens. An almost exclusive staining of proximal tubulus epithelial cells known to be precursor cells of ccRCC was observed immunohistochemically. Within the proximal tubulus cells, PTEN showed clear membrane localization. In ccRCCs, PTEN expression was markedly reduced to an average of less than 10 % compared with normal tissue as evidenced by Western blot analysis (p < 0.001). In RCCs of females, PTEN expression was more strongly reduced compared to males (p = 0.006). The degree of reduction was similar in both highly differentiated (G1) carcinomas and in less differentiated (G2 - G4) carcinomas. These observations were confirmed by immunohistochemical studies, which revealed a loss of the characteristic membrane-predominant immunostaining pattern in ccRCC. In contrast to the PTEN-positive proximal tubulus epithelial cells, the distal tubulus epithelial cells that develop into benign oncocytomas showed only very weak PTEN expression. Compared to the distal tubulus epithelial cells, no down-regulation of PTEN was seen in oncocytomas. Conclusion: We conclude that PTEN expression and PTEN membrane localization are lost during early renal cell carcinogenesis and may therefore be a valuable RCC tumor marker.

Nierenzellkarzinom - PTEN - proximale Tubulus-Epithelzellen

carcinoma - renal cell - PTEN - epithelial cell

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