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HRK inactivation associated with promoter methylation and LOH in prostate cancer
Author(s) -
Higuchi Tomonori,
Nakamura Mitsutoshi,
Shimada Keiji,
Ishida Eiwa,
Hirao Kazuya,
Konishi Noboru
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20600
Subject(s) - methylation , prostate cancer , apoptosis , dna methylation , cancer research , prostate , loss of heterozygosity , immunohistochemistry , microbiology and biotechnology , biology , medicine , cancer , gene expression , pathology , gene , allele , genetics
OBJECTIVES Recent studies in selected human tumors have demonstrated reduced expression of HRK with hypermethylation. Because no similar study has been performed specifically in prostatic lesions, we examined whether the methylation status of HRK is altered in prostate cancers. METHODS We chose to analyze the hypermethylation status of HRK , the expression of HRK protein and mRNA with 12q13.1 loss of heterozygosity (LOH) and with p53 mutation, and lesion apoptotic indices as determined by transferase‐mediated digoxigenin‐tagged 16‐desoxy‐uridine‐triphosphate nick end‐labeling (TUNEL) assays in 53 prostate cancers. RESULTS Twenty of the 53 prostate cancers (38%) demonstrated hypermethylation in either the promoter or in exon 1 and, more significantly, the loss of HRK expression observed in 14 cancers by immunohistochemistry (IHC) was associated with promoter methylation. In addition, high apoptotic indices in tumors were related to positive HRK expression. Prostate cancers demonstrating HRK methylation also showed methylation of multiple other genes, such as p14 ARF , p16 INK4a , O 6 ‐MGMT, and GTS‐P , but, with the exception of one case, p53 mutations were not detected. When compared to tumors having a Gleason score (GS) of 5–6, a significant difference in the apoptotic indices was found among prostate cancers of GS 7 ( P < 0.001) or GS 8–9 ( P = 0.007). We also detected a close correlation between the loss of HRK expression and decreased apoptosis in GS 5–6 and GS 7 tumors ( P = 0.008, P < 0.001, respectively). CONCLUSIONS HRK appears to be inactivated principally by promoter hypermethylation in prostate cancers. We further suggest that the decreased expression of HRK may play an important role in tumor progression by modulating apoptotic cell death. Prostate 68: 105–113, 2008. © 2007 Wiley‐Liss, Inc.