The hedgehog (Hh) signal pathway has recently been shown to be activated in human malignancies. However, little is known about its role in the development or patient prognosis of epithelial ovarian carcinoma. In the present study, we examined in vivo and in vitro E pithelial ovarian carcinoma, which comprises the majority of malignant ovarian tumors, is the leading cause of death from gynecologic malignancy in women.(1) The survival of ovarian carcinoma patients has not improved significantly for years, indicating that further understanding of the biology of ovarian carcinoma cells is critical for the development of new treatments against this neoplasm.(2) Several studies have reported that the poor prognosis of ovarian carcinoma is related not only to the unique metastasis but also to the high proliferative activity of carcinoma cells.(3-5) However, the molecular mechanisms of the proliferation of ovarian carcinoma cells are not fully understood. Recent studies suggest that the hedgehog (Hh) signal pathway contributes to cell proliferation and differentiation in several human neoplasms, such as pancreas, prostate and skin carcinomas.
Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.Epithelial ovarian carcinoma, which comprises the majority of malignant ovarian tumors, is the leading cause of death related to gynecological malignancies in women. 1 The survival rate of ovarian carcinoma patients has not improved significantly for years, and further understanding of the biology of ovarian carcinoma cells is critical for the development of new treatments. 2 Several studies have reported that the poor prognosis of ovarian carcinoma is related not only to the high proliferative activity of carcinoma cells, 3-6 but also to metastasis. 7-9 One important event in metastasis is the loss of adhesion between tumor cells caused by a downregulation of E-cadherin expression, which has been reported to occur via genetic or epigenetic changes. [10][11][12] Histone acetylation/deacetylation controls chromatin activity. The acetylation of histones is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs). HDACs catalyze the removal of acetyl groups on the NH2-terminal lysine residues of core nucleosomal histones and this activity is generally associated with transcriptional repression of tumor suppressors, such as p21 and E-cadherin. Through these mechanisms, HDACs act as critical regulators of cell growth, differentiation and apoptotic programs. The famil...
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