Molecular targeted therapy by inducing cancer cell senesence

答：我们已经从人类4号染色体克隆了NECC1基因，作为绒毛膜癌细胞的衰老诱导基因。我们研究了NECC1 KO(-/-)小鼠胚胎的胎盘解剖。在KO胎盘中，巨细胞层肥大和海绵滋养层形成受到抑制。NECC1在8.5-11.5DPC野生型小鼠胎盘中瞬时表达。NECC1参与了滋养层干细胞向巨细胞分化的负调控过程。B.我们从lg42区域克隆了具有诱导子宫内膜癌细胞衰老作用的EGLN1基因。EGLN1是脯氨酸羟基酶家族的一员，调节HIF1α蛋白的降解。FIH或HIFlsiRNA抑制α介导的信号转导也可诱导癌细胞衰老。在子宫内膜癌细胞中过表达EGLN1能够通过上调p21CDK抑制物来诱导细胞衰老。c.我们发现致癌的K-RAS突变体能够激活ERα。PR或显性阴性ER突变体的表达可诱导癌细胞衰老。ERα失活导致mdm2表达下调，随后p53激活，p21表达上调。我们已经证明了针对以下两个方面的新疗法的有效性：1)功能失活ERα；2)抑制mdm2蛋白表达。两种药物均能通过上调p21基因诱导癌细胞衰老。这种作用不依赖于P53。目前，我们正在计划使用丙戊酸进行临床研究。

A. We have cloned the NECCl gene from human chromosome 4 as a senescence inducing gene in choriocaracinoma cells. We investigated the placental anatomy of NECCl KO (-/-) mouse embryos. In the KO placeuta hypertrophy of giant cell layer and suppression of spongio-trophoblast layer formation were noticeable, respectively. NECCl expression was transiently detected in 8.5-11.5 dpc wild type mouse placenta. NECCl was involved in the negative regulation of differentiation from trophoblast stem cell to giant cell.B. We have cloned the EGLNl gene that has the potential to induce endometrial cancer cell senescence from lg42 region. EGLNl was a member of prolyl hydroxylase family and regulated HIF1 α protein degradation. Inhibition of HIFl α-mediated signaling by FIH or HIFlsiRNA also induced the cancer cell senescence. Overexpression of EGLNl in endometrial cancer cells was able to induce cell senescence through upregulation of p21 CDK ihibitor.C. We found the ER α activation by the oncogenic K-Ras mutant. Expression of PR or dominant-negative ER mutant elicited the cancer cell senescence. ER α inactivation resulted in the downregulation of MDM2 followed by p53 activation and subsequent p21 upregulation. We have demonstrated the efficacy of new therapies targetted i)functional inactivation of ER α and ii)suppression of MDM2 protein expression, respectively.D. We have demonstrated the anti-tumor activity of Sodium Butyrate and Valproic acid that are HDAC inhibitors. Both agents were able to induce cancer cell senescence through p21 upregulation. This effect was independent of p53. Now we are planning the clinical research by using Valproic acid.