SIGNAL TRANSDUCTION MOLECULE IN OVARIAN CARCINOGENESIS

利用RNA指纹（RAP）策略，申请人已识别

Using RNA fingerprinting (RAP) strategy, the applicant has identified a differentially expressed sequence DOC-2 which is detectable in all normal human ovarian surface epithelial cell (HOSE) cultures but not in ovarian cancer cells and tissues. When DOC-2 was transfected into the ovarian carcinom cell line SKOV3, the stable transfectants showed significantly reduced growth rate and ability to form tumors in nude mice. These data strongly suggest that DOC-2 is a signal transduction molecule and down regulation of DOC-2 may play an important role in ovarian carcinogenesis. Based on these results, it is proposed (1) to study the expression pattern of the DOC-2 gene in normal ovary and ovarian tumor tissues of different stages and histological grades by Northern and Western blot analysis, in situ hybridization and immunohistochemical detection; (2) to evaluate the role of DOC-2 as a signal transduction molecule in tumor suppression; and (3) to delineate the mechanism(s) that down regulate DOC-2 in ovarian carcinoma cells. The results from these experiments should give us insights into the growth and differentiation controlling mechanisms of DOC-2 in normal HOSE cells and explain why down-regulation of DOC-2 can result in malignant transformation of normal HOSE cells. If down-regulation of DOC-2 is shown to activate certain oncogenic signaling pathway(s) in ovarian cancer cells, therapeutic drugs that specifically target these pathways can be designed and used in the treatment of ovarian cancer. Furthermore, since up-regulation of the DOC-2 protein in ovarian carcinoma cells has been shown to inhibit their growth, strategies based on alteration in DOC-2 expression may also have therapeutic potential in ovarian malignancies.