Type II 11B-Hydroxysteroid Dehydrogenase and Colorectal Tumorigenesis

描述（由申请人提供）： 结直肠癌（CRC）是癌症死亡的主要原因，也是最可预防的癌症之一。CRC中环氧合酶-2（考克斯-2）表达增加，长期使用非甾体抗炎药（NSAID）和考克斯-2抑制剂抑制其活性可抑制CRC的发展。然而，由于长期使用NSAID和考克斯-2抑制剂而增加的副作用限制了它们在CRC的化学预防和化学治疗中的潜在用途。最近，已经提出，5-脂氧合酶（5-LOX）促进，而15-LOX抑制，结直肠肿瘤的发生。因此，为了预防CRC的发展，重要的是确定抑制考克斯-2和5-LOX并刺激15-LOX而副作用最小的方法。糖皮质激素（GC）是最有效的内源性考克斯-2抑制剂，其作用受2型11 β-羟基类固醇脱氢酶（11 ssHSD 2）的下调，该酶可抑制GC。GC也抑制5-LOX途径，但刺激15-LOX途径。11 ssHSD 2主要在经典的醛固酮敏感性上皮细胞中表达，例如在肾脏和结肠中，但也在小肠中表达。11 ssHSD 2的升高与肿瘤发生相关。我们已经发现，11 ssHSD 2抑制抑制肾皮质中的考克斯-2表达。我们假设11 ssHSD 2抑制将抑制考克斯-2和5-LOX途径，但通过升高肿瘤细胞内活性GC水平刺激15-LOX途径，从而减少结直肠肿瘤发生。我们在目前的提案中有三个具体目标：目标1将确定11 ssHSD 2抑制在肠息肉病小鼠模型中的预防和治疗效果目的2研究11 ssHSD 2对结肠癌发生的调控机制;目的3将研究5-LOX、15-LOX和考克斯-2通路在11 ssHSD 2抑制介导的腺瘤发展抑制中的相对重要性。完成目前的建议可能会指出新的策略，CRC化学预防和化疗，因为以下优点：1。甘草酸（GA）是甘草中含有的一种化合物，是一种强大的11 ssHSD 2抑制剂，无毒; 2）。由于其表达受限，预测11 ssHSD 2抑制可抑制CRC的发展，而不存在长期使用考克斯-2抑制剂造成的潜在心血管风险; 3）。GC抑制考克斯-2的表达，但不抑制考克斯-1的表达。因此，11 ssHSD 2抑制将抑制结直肠癌的发展，而没有由于NSAID抑制考克斯-1而引起的潜在副作用; 4）11 ssHSD 2抑制介导的细胞内GC升高也可能通过抑制5-LOX通路和刺激15-LOX通路来抑制结直肠肿瘤的发生。公共卫生相关性：项目叙述：尽管通过非甾体抗炎药或选择性考克斯-2抑制剂抑制考克斯-2衍生的PGE 2生物合成抑制结肠直肠肿瘤发生，但由于长期使用NSAID和考克斯-2抑制剂而增加的副作用限制了它们在CRC的化学预防和化学治疗中的潜在用途。糖皮质激素是最有效的内源性考克斯-2抑制剂，其作用受2型11 β-羟基类固醇脱氢酶下调。在目前的提案中，我们将测试是否抑制2型11 β-羟基类固醇脱氢酶活性可以提供一个新的策略，CRC化学预防和化疗的副作用最小。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the leading cause of cancer death and is one of the most preventable cancers. Cyclooxygenase-2 (COX-2) expression increases in CRC, and inhibition of its activity by chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors suppresses CRC development. However, increased side effects due to chronic use of NSAIDs and COX-2 inhibitors limit their potential use in chemoprevention and chemotherapy of CRC. Recently, it has been proposed that 5-lipoxygenase (5-LOX) promotes, while 15-LOX inhibits, colorectal tumorigenesis. Therefore, to prevent CRC development, it is important to identify means to inhibit COX-2 and 5-LOX and stimulate 15-LOX with minimal side effects. Glucocorticoids (GCs) are the most potent endogenous COX-2 inhibitors, and their actions are down-regulated by type 2 11ss-hydroxysteroid dehydrogenase (11ssHSD2), which inactivate GCs. GCs also inhibit the 5-LOX pathway but stimulate the 15-LOX pathway. 11ssHSD2 is primarily expressed in classic aldosterone-sensitive epithelia such as in the kidney and colon, but is also expressed in small intestine. Elevation of 11ssHSD2 is associated with tumorigenesis. We have found that 11ssHSD2 inhibition suppresses COX-2 expression in kidney cortex. We hypothesize that 11ssHSD2 inhibition will inhibit the COX-2 and 5-LOX pathways but stimulate the 15-LOX pathway by elevating tumor intracellular levels of active GC and will thereby reduce colorectal tumorigenesis. We have three specific aims in the current proposal: Aim 1 will determine the preventive and therapeutic effects of 11ssHSD2 inhibition in a mouse model of intestinal polyposis (Min mouse) and the preventive effect of 11ssHSD2 inhibition in CT26 tumor metastasis; Aim 2 will study the mechanisms of 11ssHSD2 regulation of colorectal tumorigenesis; and Aim 3 will investigate the relative importance of 5-LOX, 15-LOX, and COX-2 pathway in 11ssHSD2 inhibition-mediated inhibition of adenoma development. Completion of this current proposal may point to new strategies for CRC chemoprevention and chemotherapy because of the following advantages: 1. Glycyrrhizic acid (GA), a compound contained in licorice, is a powerful 11ssHSD2 inhibitor and is nontoxic; 2). Due to its restricted expression, 11ssHSD2 inhibition is predicted to suppress CRC development without the potential cardiovascular risks posed by chronic use of COX-2 inhibitors; 3). GCs suppress COX-2, but not COX-1 expression. Therefore, 11ssHSD2 inhibition will suppress CRC development without the potential side effects due to COX-1 inhibition by NSAIDs; 4) 11ssHSD2 inhibition-mediated intracellular GC elevation may also inhibit colorectal tumorigenesis through inhibition of the 5-LOX pathway and stimulation of the 15-LOX pathway. PUBLIC HEALTH RELEVANCE: Project Narrative: Although inhibition of COX-2-derived PGE2 biosynthesis by either non-steroidal anti- inflammatory drugs or selective COX-2 inhibitors suppresses colorectal tumorigenesis, increased side effects due to chronic use of NSAIDs and COX-2 inhibitors limit their potential use in chemoprevention and chemotherapy of CRC. Glucocorticoids are the most potent endogenous COX-2 inhibitors, and their actions are down-regulated by type 2 11ss-hydroxysteroid dehydrogenase. In the current proposal, we will test whether inhibition of type 2 11ss-hydroxysteroid dehydrogenase activity may provide a new strategy for CRC chemoprevention and chemotherapy with minimal side effects.