Mechanism of Granulosa Cell Differentiation and Oncogenesis

1. 人颗粒细胞类固醇生成和凋亡的分子机制。在人颗粒细胞系（HO-23）中，证实糖皮质激素和细胞外基质（ECM）促进P4的产生，而bFGF和酚酯TPA抑制P4的产生；糖皮质激素、ECM和bFGF抑制p53诱导的HO-23细胞凋亡，而TPA促进P4的产生，并且早期凋亡不中断类固醇的形成。卵巢癌新治疗策略的建立：(1)顺铂与茶碱联用的疗效：我们发现顺铂与茶碱协同作用诱导p53和HaRAS （HRP-53）突变的人卵巢癌细胞的细胞死亡，浓度低于卵巢癌治疗中通常使用浓度的3-5倍。(2)我们已经证明p53野生型耐药人卵巢癌细胞中的Xiap下调可诱导caspase-3介导的MDM2加工，导致p53含量增加和细胞凋亡。虽然在p53突变的癌细胞中单独无效，但通过反义表达抑制Xiap的含量可以显著增强野生型p53的促凋亡作用。此外，这些发现表明，Xiap可能是一个新的靶点。

1. Molecular mechanism of steroidogenesis and apoptosis in human granulosa cells.Using human granulosa cell lines (HO-23), it was confirmed that glucocorticoids and extracellular matrix(ECM) enhanced P4 production while bFGF and phorbol ester TPA suppressed it, that glucocorticoids, ECM and bFGF inhibited p53-induced apoptosis of HO-23 cells while TPA enhanced it, and that apoptosis at early stage does not interrupt steroidogenesis.2. Establishment of a new treatment strategy for ovarian cancer:(1) The Efficacy of combination of cisplatin and theophylline:We have found that cisplatin synergies with theophylline in induction of cell death in human ovarian cancerous cells with mutated p53 and HaRAS (HRP-53) in concentrations lower 3-5 times than these normally administered in ovarian cancer therapy.(2) We have demonstrated that Xiap down-regulation in p53 wild-type resistant human ovarian cancer cells induces caspase-3-mediated MDM2 processing, leading to increased p53 content and apoptosis. While ineffective alone in p53-mutant cancer cells, suppression of Xiap content by antisense expression can significant enhance the pro-apoptoic effects of wild type-p53 sense expression. In addition, these findings suggest that Xiap may be a novel target.