SIGNAL TRANSDUCTION MOLECULE IN OVARIAN CARCINOGENESIS

使用RNA指纹图谱（RAP）策略，申请人已经鉴定出 差异表达的序列DOC-2，其在所有细胞中均可检测到， 正常人卵巢表面上皮细胞（HOSE）培养物，但在 卵巢癌细胞和组织。当DOC-2转染入 卵巢癌细胞株SKOV 3，稳定转染子显示 显著降低生长速率和在裸鼠中形成肿瘤的能力 小鼠 这些数据有力地表明DOC-2是一种信号转导途径， DOC-2的表达下调可能是导致细胞凋亡的重要原因之一。 卵巢癌 基于这些结果，建议（1） 研究DOC-2基因在正常卵巢组织中的表达模式， 不同分期和组织学分级的卵巢肿瘤组织， 北方和西方印迹分析，原位杂交和 免疫组化检测DOC-2的表达;（2）探讨DOC-2作为一种免疫抑制剂在肿瘤细胞中的作用。 肿瘤抑制中信号转导分子;和（3）描绘 卵巢癌细胞DOC-2表达下调的机制。 这些实验的结果应该让我们了解 DOC-2生长和分化的调控机制 HOSE细胞，并解释为什么DOC-2的下调可以导致 正常HOSE细胞的恶性转化。 如果下调 DOC-2显示激活某些致癌信号通路， 卵巢癌细胞，专门针对这些细胞的治疗药物 可以设计这些途径并用于治疗卵巢癌。 此外，由于卵巢中DOC-2蛋白的上调， 癌细胞已被证明可以抑制其生长， DOC-2表达的改变也可能具有治疗潜力 卵巢恶性肿瘤

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.