Cancer Research UK Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Medical Sciences Building, University Walk, University of Bristol, UK.
Carcinogenesis. 2013 May;34(5):1150-7. doi: 10.1093/carcin/bgt020. Epub 2013 Jan 24.
Cyclooxygenase-2 is overexpressed in the majority of colorectal tumours leading to elevated levels of prostaglandin E2 (PGE2), promoting many hallmarks of cancer. Importantly, PGE2 is reported to enhance Wnt/β-catenin signalling in colorectal carcinoma cells and in normal haematopoietic stem cells where it promotes stem cell function. Although Wnt signalling plays a crucial role in intestinal stem cells, the relationship between PGE2 and intestinal stem cells is unclear. Given that the key intestinal cancer stem cell marker LGR5 (leucine-rich G-protein coupled receptor 5) is a Wnt target and PGE2 enhances Wnt signalling, the focus of this study was to investigate whether PGE2 regulated LGR5 expression in colorectal adenoma cells and whether LGR5 was important for tumour cell survival. PGE2 upregulated LGR5 protein in adenoma (RG/C2) and carcinoma (DLD-1) cell lines. LGR5 knockdown induced cell death in RG/C2 and AA/C1 adenoma cells, suggesting that LGR5 has an important survival-promoting role in adenoma cells. Indeed, we detected LGR5 protein expression in 4 of 4 human adenoma cell lines. Furthermore, LGR5 small interfering RNA inhibited the survival-promoting effects of PGE2 in RG/C2, suggesting that PGE2 promotes adenoma cell survival, at least in part, by increasing LGR5 expression. These studies, therefore, show the first link between PGE2 and LGR5 in human colorectal adenoma and carcinoma cells and demonstrate a survival-promoting role of LGR5. As non-steroidal anti-inflammatory drugs (NSAIDs) cause adenomas to regress in FAP patients, these studies could have important implications for the mechanism by which NSAIDs are chemopreventive, as lowering PGE2 levels could reduce LGR5 expression and survival of LGR5(+) adenoma stem cells.
环氧化酶-2 在大多数结直肠肿瘤中过度表达，导致前列腺素 E2（PGE2）水平升高，促进了癌症的许多特征。重要的是，据报道 PGE2 增强了结直肠癌细胞和正常造血干细胞中的 Wnt/β-连环蛋白信号，从而促进了干细胞功能。尽管 Wnt 信号在肠干细胞中发挥着关键作用，但 PGE2 与肠干细胞之间的关系尚不清楚。鉴于关键的肠肿瘤干细胞标志物 LGR5（富含亮氨酸的 G 蛋白偶联受体 5）是 Wnt 的靶标，并且 PGE2 增强了 Wnt 信号，本研究的重点是调查 PGE2 是否调节结直肠腺瘤细胞中的 LGR5 表达，以及 LGR5 是否对肿瘤细胞存活重要。PGE2 在上皮腺瘤（RG/C2）和癌（DLD-1）细胞系中上调 LGR5 蛋白。LGR5 敲低诱导 RG/C2 和 AA/C1 腺瘤细胞死亡，表明 LGR5 在腺瘤细胞中具有重要的促生存作用。事实上，我们在 4 个人类腺瘤细胞系中检测到了 LGR5 蛋白的表达。此外，LGR5 小干扰 RNA 抑制了 PGE2 在 RG/C2 中的促生存作用，表明 PGE2 通过增加 LGR5 表达来促进腺瘤细胞的存活，至少部分如此。因此，这些研究首次在人结直肠腺瘤和癌细胞中显示了 PGE2 与 LGR5 之间的联系，并证明了 LGR5 的促生存作用。由于非甾体抗炎药（NSAIDs）可使 FAP 患者的腺瘤消退，这些研究可能对 NSAIDs 化学预防作用的机制具有重要意义，因为降低 PGE2 水平可能会降低 LGR5 表达和 LGR5（+）腺瘤干细胞的存活。
