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

我们检测了REIC/DKK-3，一个可能的肿瘤抑制基因的候选基因，在人肾透明细胞癌(RCCC)细胞系和零星的RCCC手术标本中的表达。人肾小管上皮细胞系(Caki-1、Caki-2、ACHN和KPK-1)中REIC/DKK-3基因和蛋白的表达均降低。免疫组织化学和Western印迹分析显示，14例肾癌中分别有6例和13例的REIC/DKK-3蛋白表达水平显著降低。因此，REIC/DKK-3可能成为治疗RCCC的新的分子靶点(J.Uro.171：1314-18,2004)。我们还证明了REIC/DKK-3在人前列腺癌组织中的表达持续降低，且呈阶段依赖关系。强制表达REIC/DKK-3可诱导内源性REIC/DKK-3表达缺失的人前列腺癌细胞系的凋亡，但不能诱导表达REIC/DKK-3的正常前列腺上皮和间质细胞的凋亡。细胞凋亡与JNK活化、Bax线粒体移位、Bcl2表达减少有关。单次注射携带REIC/DKK-3的腺病毒载体对人前列腺癌异种移植瘤有显著的抗肿瘤作用。因此，REIC/DKK-3可能成为前列腺癌基因治疗的新靶点(癌症研究中心，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).