Type II 11B-Hydroxysteroid Dehydrogenase and Colorectal Tumorigenesis

项目摘要 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。 癌的环氧化酶-2（考克斯-2）在结直肠癌中表达增加， 长期使用非甾体抗炎药（NSAID）和考克斯-2抑制剂可抑制CRC 发展然而，由于长期使用NSAID和考克斯-2抑制剂， 它们在CRC的化学预防和化学治疗中的潜在用途。最近，有人提出， 5-脂氧合酶（5-LOX）促进而15-LOX抑制结肠直肠肿瘤发生。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-副作用最小的液氧。糖皮质激素（GC）是最强的内源性考克斯-2 抑制剂，其作用被2型11 β-羟基类固醇脱氢酶下调 （11 ssHSD 2），其抑制GC。GC也抑制5-LOX途径，但刺激15-LOX途径。 通路11 ssHSD 2主要在典型的醛固酮敏感性上皮细胞中表达，例如在 在肾脏和结肠中表达，但也在小肠中表达。11 ssHSD 2的升高与 肿瘤发生我们已经发现，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， 通过升高肿瘤细胞内活性GC水平刺激15-LOX途径， 从而减少结肠直肠肿瘤发生。在目前的建议中，我们有三个具体目标： 将确定11 ssHSD 2抑制在以下小鼠模型中的预防和治疗效果： 肠息肉病（Min小鼠）和11 ssHSD 2抑制在CT 26肿瘤中的预防作用 目的2研究11 ssHSD 2调控结直肠肿瘤发生的机制; 目的3研究5-LOX、15-LOX和考克斯-2通路在11 ssHSD 2中的相对重要性 抑制介导的腺瘤发展抑制。完成目前的提案可能会表明， CRC化学预防和化疗的新策略，因为有以下优点： 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 没有长期使用考克斯-2抑制剂造成的潜在心血管风险的发展; 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CRC 由于NSAID抑制考克斯-1，无潜在副作用; 4）11 ssHSD 2 抑制介导的细胞内GC升高也可以通过以下途径抑制结肠直肠肿瘤的发生： 抑制5-LOX途径和刺激15-LOX途径。

Project Summary 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.