Research on Functional Analysis and Clinical application of New Tumor-associated Gene (REIC) in Urogenital Cancer

我们检测了REIC/Dkk-3（一种可能的肿瘤抑制基因候选者）在人肾透明细胞癌（RCCC）细胞系和散发性RCCC手术标本中的表达。在人RCCC细胞系（Caki-1、Caki-2、ACHN和KPK-1）中，REIC/Dkk-3 mRNA和蛋白的表达被证实降低。免疫印迹分析和免疫组化显示，REIC/Dkk-3蛋白水平显着下降，分别在6的7和13的14例RCCC分析。因此，REIC/Dkk-3可能是针对RCCC的治疗措施的新的分子靶点（J.Urol.171：1314- 18，2004）。在缺乏内源性REIC/Dkk-3表达的人前列腺癌细胞系中，REIC/Dkk-3的强制表达诱导凋亡，但在REIC/Dkk-3-熟练的正常前列腺上皮细胞和基质细胞中不诱导凋亡。细胞凋亡涉及JNK激活、Bax的线粒体易位和Bcl-2的减少。单次注射携带REIC/Dkk-3的腺病毒载体对异种移植的人前列腺癌显示出显著的抗肿瘤作用。因此，REIC/Dkk-3可能成为前列腺癌基因治疗的新靶点（Cancer Res，65：9617- 9622，2005）。

We examined the expression of REIC/Dkk-3, a possible candidate for a tumor suppressor gene, in human renal clear cell carcinoma (RCCC) cell lines and sporadic RCCC surgical specimens. The decreased expression of REIC/Dkk-3 mRNA and protein in human RCCC cell lines (Caki-1,Caki-2,ACHN and KPK-1) were confirmed. Western blot analysis and immunohistochemistry revealed a significant decrease in REIC/Dkk-3 protein levels in 6 of the 7 and 13 of the 14 RCCC cases analyzed, respectively. Thus, REIC/Dkk-3 could be a new molecular target for therapeutic measures against RCCC (J.Urol.171:1314-18,2004).We also demonstrated that expression of REIC/Dkk-3 was consistently reduced in human prostate cancer tissues in a stage-dependent manner. Forced expression of REIC/Dkk-3 induced apoptosis in human prostate cancer cell lines lacking endogenous REIC/Dkk-3 expression but not in REIC/Dkk-3-proficient normal prostate epithelial and stromal cells. The apoptosis involved JNK activation, mitochondrial translocation of Bax, and reduction of Bcl-2. A single injection of an adenovirus vector carrying REIC/Dkk-3 showed a dramatic anti-tumor effect on a xenotransplanted human prostate cancer. Thus, REIC/Dkk-3 could be a novel target for gene-based therapy of prostate cancer (Cancer Res, 65:9617-9622,2005).