Dixon Dan A, Blanco Fernando F, Bruno Annalisa, Patrignani Paola
Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS 66106, USA.
Recent Results Cancer Res. 2013;191:7-37. doi: 10.1007/978-3-642-30331-9_2.
The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states and a large amount of evidence has demonstrated constitutive COX-2 expression to be a contributing factor promoting colorectal cancer (CRC). Various genetic, epigenetic, and inflammatory pathways have been identified to be involved in the etiology and development of CRC. Alteration in these pathways can influence COX-2 expression at multiple stages of colon carcinogenesis allowing for elevated prostanoid biosynthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the post-transcriptional level through various RNA sequence elements present within the mRNA 3' untranslated region (3'UTR). A conserved AU-rich element (ARE) functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. Specific microRNAs (miRNAs) bind regions within the COX-2 3'UTR and control COX-2 expression. In this chapter, we discuss novel insights in the mechanisms of altered post-transcriptional regulation of COX-2 in CRC and how this knowledge may be used to develop novel strategies for cancer prevention and treatment.
环氧化酶-2（COX-2）在致病状态下催化前列腺素形成的限速步骤，大量证据表明COX-2的组成性表达是促进结直肠癌（CRC）的一个因素。多种遗传、表观遗传和炎症途径已被确定参与CRC的病因学和发展。这些途径的改变可在结肠癌发生的多个阶段影响COX-2的表达，从而使肿瘤微环境中前列腺素生物合成增加。在正常细胞中，COX-2的表达水平通过存在于mRNA 3'非翻译区（3'UTR）内的各种RNA序列元件在转录后水平受到有效调控。一个保守的富含AU元件（ARE）通过与各种RNA结合蛋白结合来靶向COX-2 mRNA，使其快速降解并抑制翻译，从而影响COX-2 mRNA的命运。特定的微小RNA（miRNA）与COX-2 3'UTR内的区域结合并控制COX-2的表达。在本章中，我们将讨论CRC中COX-2转录后调控改变机制的新见解，以及如何利用这些知识开发癌症预防和治疗的新策略。
