Early oncogenic events and defective apoptosis in prostate cancer

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Surgical Science

Sammanfattning: Prostate cancer is one of the most common malignancies in males in the Western world. Although the mechanisms are unclear, it is generally believed that the accumulation of genetic alterations leads to the tumor formation. My studies were aimed to define genetic events leading to the development and progression of prostate cancer, and to explore their biological and therapeutic significance. Ezrin, a member of the Ezrin-Raxidin-Moesin(ERM) family, is involved in cell shaping and signalling. We studied its protein expression and gene copy number in 19 cases of high-grade prostatic intraepithelial neoplasia (HGPIN) with concomitant prostate cancer. We found the immunoreactivity to be absent or weak in benign prostate epithelial cells, weak or moderate in cancer, but strong in HGPIN. No alterations in the gene copy number were detected by FISH technique. The data indicate that the aberrant expression of ezrin may be involved in the pathogenesis of prostate cancer and be useful in the diagnosis of HGPIN. Pim-1, an oncogene product of serine/threonine kinase, plays an important role in apoptosis, cell cycle, and transcriptional regulation. Immunohistochemical analysis was used to test pim1 expression in HGPIN and in cancer from 121 specimens. Moderate to strong staining was observed in 68% of cancers and 97% of HGPIN, negative or weak in benign glands. Pim-1 was overexpressed in HGPIN compared to cancer in 65% of the cases. The data suggest that pim-1 overexpression in HGPIN may be an early event in the development of prostate malignancy and provides supplementary information for distinguishing HGPIN from benign epithelium. During oncogenic processes, aberrant DNA methylation frequently occurs, thereby leading to silencing of sets of genes involved in cell cycle regulation, apoptosis, and other biological functions. In our study, prostate cancer DU145 cells were grown in the presence of the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5'-aza), followed by treatment with different doses of cisplatin. The treatment of the cells with 5'-aza followed by cisplatin induced significant cell apoptosis, which suggested that suppression of DNA methylation was capable of enhancing sensitivity of prostate cancer DU145 cells to cytotoxic agent---cisplatin. The X-linked inhibitor of apoptosis protein (XIAP) suppresses cell apoptosis while the XIAPassociated factor 1 (XAF1) promotes apoptosis. We studied XAF1 expression in prostate cancer cells. Compared to normal tissues where a full-length of XAF1 mRNA is predominant, PC3, LNCaP, and DU145 cells expressed no or only short forms XAF1 transcripts. Inhibition of DNA methylation led to a switch to full length of XAF1 mRNA expression. Both short forms and full-length forms were detectable in primary prostate tumors, suggesting that splicing alterations of the XAF1 transcript may occur during the development of prostate cancers due to aberrant DNA methylation. In summary, our data suggest the activation of the Ezrin and Pim-1 genes may be early oncogenic events in the development of prostate cancer, and that the alternative XAF1 mRNA splicing and aberrant DNA methylation are linked to prostate cancer cell survival. These findings have important biological and clinical implications.

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