Ovarian cancer (OC) is one of the most threatening malignant tumors in females due to the frequent occurrence of metastasis that precedes diagnosis. The prevention and treatment of OC metastasis continues to provide a significant molecular challenge. To develop new anti-metastatic therapies, we need to understand the biological and biochemical mechanisms of metastasis. Although many genetic events promote metastasis, several genes show relatively reduced expression levels in metastatic tumor cells. Re- expression of a metastasis-suppressor gene in metastatic tumor results in a significant reduction in metastatic behavior in vivo. The cellular functions of a metastasis suppressor gene, NM23-H2 are not known in ovarian cancer. Recently, we have demonstrated a) reduced expression of NM23-H2 in ovarian cancer (OVCA) cell lines compared to normal human ovarian surface epithelial (HOSE) cell lines, b) increased transcription of NM23-H2 in epithelial OVCA cells when treated with progesterone and c) marked decrease in cell invasiveness when NM23-H2 was re-expressed in OVCA cells. Based on these preliminary data, we hypothesize that down regulation of NM23 gene is involved in the pathogenesis of epithelial OC and elevation of metastasis suppressor gene expression in tumor cells will halt metastatic colonization and have a clinical benefit.
Two aims have been put forth to test the hypothesis:
Specific Aim 1 : Determination of the NM23-H2 protein in a variety of ovarian cancer tissue sections and correlation of its expression with the stage of disease.
Specific Aim 2 : To determine 1) Whether NM23-H2 re-expression will decrease invasive behavior of OVCA cells in vitro and in vivo and 2) To establish whether progesterone injections will decrease metastasis potential of OVCA cells by up-regulating NM23-H2 expression in vivo. Reactivation of NM23-H2 gene may yield a potential therapeutic intervention for ovarian cancer. ? ? ?
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