Green tea polyphenol (
GTP) suppresses
carcinogenesis and aggressiveness in many types of
malignancies including
bladder cancer. However, the mechanistic basis of these effects is not well understood. This was investigated in the present study using a mouse model of chemically induced
bladder cancer. C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl)
nitrosamine (BBN)
solution for 14-24 weeks. Mice in the BBN +
GTP group (n = 47) were also treated with 0.5%
GTP solution over the same period.
Tumor cell proliferation and microvessel density were evaluated along with immunohistochemical analysis of human
antigen (Hu)R,
vascular endothelial growth factor (
VEGF)-A,
cyclooxygenase (COX)-2, and hemeoxygenase (HO)-1 expression. Cytoplasmic HuR expression in
cancer cells was higher at 14 and 24 weeks in the BBN than in the control group and was associated with increased invasion of
tumor cells in muscle. However, these effects were not observed in the BBN +
GTP group. A multivariate analysis of
GTP intake and cytoplasmic HuR expression revealed that
GTP was independently associated with COX-2 and HO-1 expression, while cytoplasmic HuR expression was associated with COX-2 and
VEGF-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation and that of
VEGF-A and HO-1 was associated with angiogenesis. Nuclear HuR expression was not associated with any parameters such as
carcinogenesis, muscle invasion, and
GTP intake. These results indicate that
GTP intake can suppress
tumor progression and malignant behavior in an animal model of
bladder cancer. We also speculate that
GTP directly and indirectly suppresses
tumor cell proliferation and angiogenesis via HuR-related pathways in
bladder cancer.