School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
Clin Cancer Res. 2011 Dec 15;17(24):7551-62. doi: 10.1158/1078-0432.CCR-11-1026. Epub 2011 Oct 6.
PRKCDBP is a putative tumor suppressor in which alteration has been observed in several human cancers. We investigated expression and function of PRKCDBP in colorectal cells and tissues to explore its candidacy as a suppressor in colorectal tumorigenesis.
Expression and methylation status of PRKCDBP and its effect on tumor growth were evaluated. Transcriptional regulation by NF-κB signaling was defined by luciferase reporter and chromatin immunoprecipitation assays.
PRKCDBP expression was hardly detectable in 29 of 80 (36%) primary tumors and 11 of 19 (58%) cell lines, and its alteration correlated with tumor stage and grade. Promoter hypermethylation was commonly found in cancers. PRKCDBP expression induced the G(1) cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses. PRKCDBP was induced by TNFα, and its level correlated with tumor cell sensitivity to TNFα-induced apoptosis. PRKCDBP induction by TNFα was disrupted by blocking NF-κB signaling while it was enhanced by RelA transfection. The PRKCDBP promoter activity was increased in response to TNFα, and this response was abolished by disruption of a κB site in the promoter. PRKCDBP delayed the formation and growth of xenograft tumors and improved tumor response to TNFα-induced apoptosis.
PRKCDBP is a proapoptotic tumor suppressor which is commonly altered in colorectal cancer by promoter hypermethylation, and its gene transcription is directly activated by NF-κB in response to TNFα. This suggests that PRKCDBP inactivation may contribute to tumor progression by reducing cellular sensitivity to TNFα and other stresses, particularly under chronic inflammatory microenvironment.
PRKCDBP 是一种假定的肿瘤抑制因子，在几种人类癌症中观察到其改变。我们研究了 PRKCDBP 在结直肠细胞和组织中的表达和功能，以探讨其作为结直肠肿瘤发生抑制因子的候选物。
评估 PRKCDBP 的表达和甲基化状态及其对肿瘤生长的影响。通过荧光素酶报告和染色质免疫沉淀实验来定义 NF-κB 信号转导的转录调节。
在 80 个原发性肿瘤中的 29 个（36%）和 19 个细胞系中的 11 个（58%）中几乎检测不到 PRKCDBP 的表达，其改变与肿瘤分期和分级相关。癌症中常见启动子甲基化。PRKCDBP 的表达诱导 G1 细胞周期停滞，并增加细胞对各种凋亡应激的敏感性。PRKCDBP 由 TNFα 诱导，其水平与肿瘤细胞对 TNFα 诱导的细胞凋亡的敏感性相关。PRKCDBP 诱导由 NF-κB 信号转导阻断而中断，而由 RelA 转染增强。PRKCDBP 启动子活性响应 TNFα 而增加，并且该反应被启动子中 κB 位点的破坏所消除。PRKCDBP 延迟异种移植肿瘤的形成和生长，并改善肿瘤对 TNFα 诱导的细胞凋亡的反应。
PRKCDBP 是一种促凋亡的肿瘤抑制因子，在结直肠癌中通常通过启动子甲基化改变，其基因转录在受到 TNFα 刺激时直接由 NF-κB 激活。这表明 PRKCDBP 的失活可能通过降低细胞对 TNFα 和其他应激的敏感性，特别是在慢性炎症微环境下，有助于肿瘤的进展。
