The role of hyaluronan (HA), serum-derived HA-associated protein (SHAP)-HA complex and hyaluronan synthase (HAS) in endometrial carcinomas was investigated. The relationship of metalloproteinase (MMP) and its inhibitor (TIMP) with HA and the SHAP-HA complex was also examined. The expression of HAS1 was related to the depth of myometrial invasion and lymph-vascular space involvement. The serum levels of HA, SHAP-HA complex, MMP-9, and TIMP-1 were increased in related with the depth of myometrial invasion, histological grade and lymph-vascular space involvement. They were also higher in the HAS1-positive group compared to -negative group. The serum concentrations of HA and SHAP-HA complex had a significant correlation with the MMP-9 and TIMP-1. The patients with elevated SHAP-HA complex had the shorter disease-free survival. The multivariate analysis revealed that the SHAP-HA complex was the independent variable for disease-free survival of endometrial cancer patients. In conclusion, the elevation of serum SHAP-HA complex depended on the HAS1 expression and the SHAP-HA complex is a useful marker to predict disease recurrence in endometrial cancer patients. The SHAP-HA complex may promote the lymph-vascular space involvement and the synthesis and activation of MMP-9 and TIMP-1 in the progression of endometrial cancer. 1. Introduction The incidence rate for endometrial cancer has been increasing in Japan [1]. Clinicopathological studies show that poor prognosis is related to cervical invasion of malignant cells, deep myometrial invasion of malignant cells, lymph node metastasis, and lymph-vascular space involvement of malignant cells [2, 3]. The multistage process of tumor invasion and metastasis depends on several mechanisms, including the stimulation of cell growth by growth factors, destruction of the extracellular matrix by proteolytic enzymes, neovascularization due to the presence of angiogenic factors, and cell to cell or stroma adhesion regulated by cell adhesion molecules. Hyaluronan (HA) is an extracellular polysaccharide typically present in the extracellular matrix of some epithelial and neural tissues. HA is particularly abundant in connective tissues. HA controls cell migration, differentiation, and proliferation, thereby influencing tissue morphogenesis, wound healing, and tumor growth [4, 5]. HA levels correlate with the invasiveness and metastatic capacity of tumor cells [6]. Increased HA concentrations may help invasion by providing a less dense matrix for cancer cells [7], stimulating cancer cell motility, and forming an immunoprotective
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