SIGNAL TRANSDUCTION MOLECULE IN OVARIAN CARCINOGENESIS

使用RNA指纹(RAP)策略，申请人已识别 ALL中可检测到的差异表达序列DOC-2 正常人卵巢表面上皮细胞(HSOSE)培养 卵巢癌细胞和组织。将DOC-2基因导入人卵巢癌细胞株 卵巢癌细胞株SKOV3的稳定表达 显著降低裸体的生长速度和成瘤能力 老鼠。这些数据有力地表明DOC-2是一种信号转导 DOC-2的分子和下调可能在其中起重要作用 卵巢癌的发生。基于这些结果，建议(1) DOC-2基因在正常卵巢和正常卵巢中的表达 不同分期、不同组织学分级的卵巢肿瘤组织 Northern和Western印迹分析，原位杂交和 免疫组织化学检测；(2)评价DOC-2作为一种 肿瘤抑制中的信号转导分子；(3)勾画 下调卵巢癌细胞DOC-2的作用机制(S)。 这些实验的结果应该会让我们深入了解 DOC-2在正常人体内的生长分化调控机制 并解释为什么DOC-2的下调会导致 正常软管细胞恶变。如果下调了对 DOC-2可激活某些致癌信号通路(S) 卵巢癌细胞，专门针对这些细胞的治疗药物 途径可以设计并用于卵巢癌的治疗。 此外，由于DOC-2蛋白在卵巢中的上调 肿瘤细胞已被证明可以抑制其生长，基于 DOC-2表达的改变也可能具有治疗潜力 在卵巢恶性肿瘤中。

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.