Hypermethylation of the CD44 gene is associated with progression and metastasis of human prostate cancer.
BACKGROUND
CD44 is a metastasis suppressor gene for prostate cancer and the down-regulation of CD44 and its variants is associated with the progression of prostate cancer. Also, hypermethylation of the CpG islands of the CD44 gene is closely associated with transcriptional inactivation, resulting in the decreased expression of CD44. To clarify the exact role of methylation status of CpG islands of CD44 gene in the progression and metastasis of prostate cancer, we investigated the methylation status of this gene in primary and metastatic human prostate tumors obtained from surgery or autopsy.


METHODS
We examined 97 samples from 40 Japanese patients with adenocarcinoma of the prostate. Tumor tissues were obtained from radical prostatectomy specimens from eight patients with stage B, 12 patients with stage C and three patients with stage D1 and at autopsy from 17 hormone-refractory metastatic cases, who had initially responded to the therapy and thereafter relapsed. Distant metastatic tissues were also obtained at autopsy (i.e., liver, lung, kidney, mammary gland, and pelvic lymph nodes) from 10 of 17 hormone-refractory cases. We analyzed the hypermethylation status of CD44 promotor region by PCR using genomic DNAs digested with the m(5)C-sensitive restriction enzyme HpaII.


RESULTS
The correlation between the methylation status of CD44 gene and the stage progression of prostate cancer was statistically significant (P = 0.0438). In two of 10 hormone-refractory cases, a comparison of the methylation status of the CD44 gene in metastases to that in primary tumors revealed interfocal heterogeneity of CD44 methylation status.


CONCLUSIONS
These results indicate an important role of CD44 methylation in the progression and metastasis of prostate cancer, although the amount of methylational heterogeneity is substantial among metastatic sites within the same patient.
Kito
H
H
Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Suzuki
H
H
Ichikawa
T
T
Sekita
N
N
Kamiya
N
N
Akakura
K
K
Igarashi
T
T
Nakayama
T
T
Watanabe
M
M
Harigaya
K
K
Ito
H
H
D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D018960:Hyaluronan Receptors