Wang Q, Sun Z, Yang H-S
Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY, USA.
Oncogene. 2008 Mar 6;27(11):1527-35. doi: 10.1038/sj.onc.1210793. Epub 2007 Sep 10.
Programmed cell death 4 (Pdcd4) is a tumor suppressor that inhibits neoplastic transformation and tumor invasion. Tissue microarray analysis showed that Pdcd4 expression is downregulated in colon adenocarcinoma and carcinoma relative to adjacent normal tissues. To address the issue of whether reduced Pdcd4 expression is sufficient to promote tumor progression, we knocked down Pdcd4 expression in colon tumor HT29 cells using pdcd4 short hairpin RNA (shRNA). Pdcd4 knockdown results in a fibroblast-like transition, while the control cells (expressing LacZ shRNA) remain as clumped similar to the parental cells. In addition, expression of pdcd4 shRNA in HT29 cells promotes invasion. In an effort to characterize the molecular mechanism underlying these observations, we discovered that knockdown of Pdcd4 results in reduction of E-cadherin expression, and accumulation of active beta-catenin in the nucleus. The active beta-catenin binds with T-cell factor 4 (Tcf4) and activates beta-catenin/Tcf-dependent transcription. Furthermore, Pdcd4 knockdown dramatically increases AP-1-dependent transcription. Thus, the mechanism by which reduced Pdcd4 expression promotes invasion appears to involve the activation of beta-catenin/Tcf and AP-1-dependent transcription.
程序性细胞死亡4(Pdcd4)是一种肿瘤抑制因子,可抑制肿瘤转化和肿瘤侵袭。组织微阵列分析显示,与相邻正常组织相比,结肠腺癌和癌组织中Pdcd4的表达下调。为了解决Pdcd4表达降低是否足以促进肿瘤进展这一问题,我们使用pdcd4短发夹RNA(shRNA)敲低结肠肿瘤HT29细胞中Pdcd4的表达。敲低Pdcd4导致细胞向成纤维细胞样转变,而对照细胞(表达LacZ shRNA)仍像亲代细胞一样聚集在一起。此外,HT29细胞中pdcd4 shRNA的表达促进细胞侵袭。为了阐明这些观察结果背后的分子机制,我们发现敲低Pdcd4会导致E-钙黏蛋白表达降低,并且活性β-连环蛋白在细胞核中积累。活性β-连环蛋白与T细胞因子4(Tcf4)结合并激活β-连环蛋白/Tcf依赖的转录。此外,敲低Pdcd4会显著增加AP-1依赖的转录。因此,Pdcd4表达降低促进侵袭的机制似乎涉及β-连环蛋白/Tcf和AP-1依赖转录的激活。