The hypoxia-inducible factor (HIF)-1a, which has a major role in cell adaptation to hypoxia, is mainly regulated at post-translational levels. Recently, HIF-1a mRNA was also shown to be upregulated by several signal pathways under normoxic conditions. Here we focused on relationships of HIF-1a with NF-kB and b-catenin signaling in endometrial carcinomas (Em Cas). Long-term exposure of Ishikawa cells to cobalt chloride (CoCl 2 ), which is known to mimic the effect of hypoxia, caused a decrease in the growth, along with increased HIF-1a protein but not mRNA expression. In contrast, short-term exposure resulted in a rapid and transient increase in HIF-1a mRNA expression along with stabilization of nuclear NF-kB/p65 (p65). Transfection of p65 increased HIF-1a expression through activation of the promoter, whereas overexpression of HIF-1a also activated NF-kB-dependent transcription, indicating the existence of a positive feedback loop. In addition, HIF-1a was indirectly associated with nuclear b-catenin through interactions with p300, leading to slight enhancement of both HIF-1a-and b-catenin-mediated transcriptional activity. In clinical samples, biphasic upregulation of HIF-1a expression was observed in normal endometrial glandular components during the menstrual cycle, with the labeling indices showing significantly higher values in the early secretory stage. Significantly higher values for phosphorylated p65 and nuclear b-catenin were also observed in HIF-1a-positive than -negative lesions of Em Cas, in contrast to significantly lower Ki-67 status. These data therefore suggest that transcriptional associations with HIF-1a and NF-kB, as well as b-catenin/p300 complexes, may contribute to modulation of changes in tumor cell kinetics in response to a hypoxic condition in Em Cas.

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Adjuvant chemotherapy was insufficient to reduce the incidence of distant recurrence. The prognosis of patients recurred within regional LN and/or vagina was significantly better than that of patients with recurrence in other lesions because of treatment with surgery and/or radiotherapy. The disease-free interval was a significant prognostic factor for REC patients.

These findings provided evidence that the balance among expression level of survivin variants may contribute to modulation of cell kinetics in Em Ca cells.