Ovarian endometrial
cysts cause some kinds of
ovarian cancer, and
iron is considered as one factor of
carcinogenesis. In contrast,
hypoxia is associated with progression, angiogenesis,
metastasis, and resistance to
therapy in
cancer. We investigated
hypoxia-induced perturbation of
iron homeostasis in terms of labile
iron,
iron deposition, and
iron regulatory protein (IRP) in ovarian endometrial
cysts.
Iron deposition, expression of IRPs, and a
protein marker of
hypoxia in human ovarian endometrial
cysts were analyzed histologically. The concentration of free
iron and the pO2 level of the cyst fluid of human
ovarian cysts (n = 9) were measured. The expression of IRP2 under
hypoxia was investigated in vitro by using Ishikawa cells as a model of endometrial cells.
Iron deposition and the expression of IRP2 and
Carbonic anhydrase 9 (CA9) were strong in endometrial stromal cells in the human ovarian endometrial
cysts. The average concentration of free
iron in the cyst fluid was 8.1 ± 2.9 mg/L, and the pO2 was 22.4 ± 5.2 mmHg. A cell-based study using Ishikawa cells revealed that IRP2 expression was decreased by an overload of Fe(II) under normoxia but remained unchanged under
hypoxia even in the presence of excess Fe(II). An increase in the expression of IRP2 caused upregulation of intracellular
iron as a result of the response to
iron deficiency, whereas the
protein was degraded under
iron-rich conditions. We found that
iron-rich regions existed in ovarian endometrial
cysts concomitantly with the high level of IRP2 expression, which should generally be decomposed upon an overload of
iron. We revealed that an insufficient level of
oxygen in the
cysts is the main factor for the unusual stabilization of IRP2 against
iron-mediated degradation, which provides aberrant uptake of
iron in ovarian endometrial stromal cells and can potentially lead to
carcinogenesis.