University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Cancer Res. 2010 Mar 1;70(5):1766-72. doi: 10.1158/0008-5472.CAN-09-3263. Epub 2010 Feb 9.
Constitutive activation of the nuclear factor-kappaB (NF-kappaB) transcription factor plays a key role in chronic colonic inflammation and colon tumorigenesis. However, the mechanisms by which the tightly regulated NF-kappaB pathway becomes constitutively activated during colonic pathogenesis remain obscure. Here, we report that PDLIM2, an essential terminator of NF-kappaB activation, is repressed in various human colorectal cancer cell lines, suggesting one important mechanism for the constitutive activation of NF-kappaB. Indeed, expression of exogenous PDLIM2 inhibited constitutive NF-kappaB activation in these colorectal cancer cells. Importantly, the PDLIM2 expression was sufficient to suppress in vitro anchorage-independent growth and in vivo tumor formation of these malignant cells. We have further shown that the PDLIM2 repression involves promoter methylation. Accordingly, treatment of the colorectal tumor cell lines with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored PDLIM2 expression and resulted in growth arrest. These studies thus provide new mechanistic insights into colon tumorigenesis by identifying a novel tumor suppressor role for PDLIM2.
核因子-κB（NF-κB）转录因子的组成性激活在慢性结肠炎症和结肠癌发生中起着关键作用。然而，在结肠发病过程中，NF-κB 途径如何被严格调控而发生组成性激活仍不清楚。在这里，我们报告称，PDLIM2 是 NF-κB 激活的必需终结者，在各种人结肠癌细胞系中受到抑制，这表明 NF-κB 的组成性激活的一个重要机制。事实上，外源性表达 PDLIM2 抑制了这些结肠癌细胞中 NF-κB 的组成性激活。重要的是，PDLIM2 的表达足以抑制这些恶性细胞体外无锚定依赖性生长和体内肿瘤形成。我们进一步表明，PDLIM2 的抑制涉及启动子甲基化。因此，用 DNA 甲基转移酶抑制剂 5-氮杂-2'-脱氧胞苷处理结肠肿瘤细胞系可恢复 PDLIM2 的表达，并导致生长停滞。这些研究通过鉴定 PDLIM2 的新的肿瘤抑制作用，为结肠癌发生提供了新的机制见解。
