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，也是最可预防的疾病之一。 癌症。环氧合酶-2(COX-2)在结直肠癌中的表达增加，并抑制其活性 长期使用非类固醇抗炎药(NSAIDs)和COX-2抑制剂抑制大肠癌 发展。然而，由于长期使用非甾体抗炎药和COX-2抑制剂而增加的副作用限制了 它们在结直肠癌化学预防和化疗中的潜在应用。最近，有人提出， 5-脂氧合酶(5-LOX)促进结直肠肿瘤的发生，而15-LOX抑制结直肠肿瘤的发生。因此，要 预防结直肠癌的发展，重要的是找出抑制COX-2和5-LOX的方法并刺激 15-LOX，副作用最小。糖皮质激素(GC)是最有效的内源性COX-2 抑制物，其作用受2型11ss-羟基类固醇脱氢酶下调 (11ssHSD2)，使GC失活。GCS还抑制5-LOX途径，但刺激15-LOX途径 路径。11ssHSD2主要在经典的醛固酮敏感上皮细胞中表达，如在 肾和结肠，但也表达在小肠。11ssHSD2的高程与 肿瘤发生学。我们发现11ssHSD2抑制可抑制肾皮质COX-2的表达。 我们假设11ssHSD2抑制将抑制COX-2和5-LOX通路，但 通过提高肿瘤细胞内活性GC和Will水平来刺激15-LOX途径 从而减少结直肠肿瘤的发生。我们在目前的提案中有三个具体目标：目标1 将确定11ssHSD2抑制在小鼠模型中的预防和治疗作用 肠息肉病(闽鼠)及11ssHSD2抑制对CT26肿瘤的预防作用 目标2将研究11ssHSD2调控结直肠肿瘤发生的机制；以及 目的3研究5-LOX、15-LOX和COX-2通路在11ssHSD2中的相对重要性 抑制介导性抑制腺瘤的发展。完成此当前提案可能会指出 结直肠癌化学预防和化疗的新战略，因为有以下优势： 1.甘草酸是甘草中的一种化合物，是一种强大的11ssHSD2抑制剂，是一种 2)无毒；由于其表达受限，11ssHSD2的抑制被预测为抑制CRC 没有长期使用COX-2抑制剂带来的潜在心血管风险的发展；3)。 GCS抑制COX-2的表达，但不抑制COX-1的表达。因此，11ssHSD2抑制将抑制CRC 无NSAIDs抑制COX-1的潜在副作用的开发；4)11ssHSD2 抑制介导的细胞内GC升高也可能通过以下途径抑制结直肠癌的发生 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.