Moore Amy E, Greenhough Alexander, Roberts Heather R, Hicks Diane J, Patsos Helena A, Williams Ann C, Paraskeva Christos
Cancer Research UK Colorectal Tumour Biology Group, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, UK.
Carcinogenesis. 2009 Oct;30(10):1796-804. doi: 10.1093/carcin/bgp183. Epub 2009 Jul 28.
Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E(2) (PGE(2)) levels. PGE(2) signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE(2) inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE(2) accumulation. The hepatocyte growth factor (HGF) receptor, Met, is frequently over-expressed in colorectal tumours and promotes cancer growth, metastasis and resistance to therapy, although the mechanisms for this have not been fully elucidated. Here, we report that HGF/Met signalling can promote PGE(2) biogenesis in colorectal cancer cells via COX-2 up-regulation and 15-PGDH down-regulation at the protein and messenger RNA level. Pharmacological inhibition of MEK and PI3K suggested that both extracellular signal-regulated kinase (ERK) and AKT signalling are required for COX-2 protein up-regulation and 15-PGDH down-regulation downstream of Met. Notably, inhibition of Met with the small molecule inhibitor SU11274 reduced COX-2 expression and increased 15-PGDH expression in high Met-expressing cells. We also show that hypoxia potentiated HGF-driven COX-2 expression and enhanced PGE(2) release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE(2) pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE(2) biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer.
有证据表明，环氧化酶（COX）-2通过提高前列腺素E2（PGE2）水平，在促进结直肠癌发生过程中起关键作用。PGE2信号传导与结直肠癌细胞的存活、增殖和侵袭密切相关。最近，也有研究表明，由烟酰胺腺嘌呤二核苷酸（NAD+）依赖性15-羟基前列腺素脱氢酶（15-PGDH）介导的PGE2失活减少会促进肿瘤内PGE2的积累。肝细胞生长因子（HGF）受体Met在结直肠癌中经常过度表达，并促进癌症生长、转移和对治疗的抗性，尽管其机制尚未完全阐明。在此，我们报告HGF/Met信号传导可通过在蛋白质和信使RNA水平上上调COX-2和下调15-PGDH，促进结直肠癌细胞中PGE2的生物合成。对MEK和PI3K的药理学抑制表明，细胞外信号调节激酶（ERK）和AKT信号传导都是Met下游COX-2蛋白上调和15-PGDH下调所必需的。值得注意的是，用小分子抑制剂SU11274抑制Met可降低高Met表达细胞中COX-2的表达，并增加15-PGDH的表达。我们还表明，缺氧增强了HGF驱动的COX-2表达，并增强了PGE2的释放。此外，抑制COX-2可阻碍HGF的促生长作用，这表明COX-2/PGE2途径是HGF/Met信号传导的重要介质。这些数据揭示了HGF/Met信号传导在促进结直肠癌细胞中PGE2生物合成方面的关键作用。针对这两个重要途径之间的相互作用进行靶向治疗，可能对结直肠癌的治疗有用。
