Type II 11B-Hydroxysteroid Dehydrogenase and Colorectal Tumorigenesis

II 型 11B-羟基类固醇脱氢酶与结直肠肿瘤发生

• 批准号: 8043556
• 负责人: Mingzhi Zhang
• 金额: $ 31.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043556
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Adenocarcinoma Cell; Adverse effects; Aldosterone; Anabolism; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Attenuated; Cancer Etiology; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Colon; Colon Adenocarcinoma; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Coxibs; Development; Dinoprostone; Epithelial Cells; Epithelium; Genetic; Glucocorticoid Receptor; Glucocorticoids; Glycyrrhizic Acid; Growth and Development function; Health; Hydroxysteroid Dehydrogenases; Intestinal Polyposis; Intestines; Kidney; Knock-out; Lead; Licorice; Lipoxygenase; Lipoxygenase 1; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Mus; Neoplasm Metastasis; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention; Preventive; Rattus; Regulation; Relative (related person); Small Intestines; Testing; Therapeutic Effect; Tissues; United States; adenoma; cancer chemoprevention; cardiovascular risk factor; chemotherapy; cyclooxygenase 1; cyclooxygenase 2; gastrointestinal; inhibitor/antagonist; kidney cortex; knock-down; mouse model; prevent; tumor; tumor growth; tumorigenesis

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.

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。环氧合酶-2(COX-2)在结直肠癌中的表达增加，长期使用非类固醇抗炎药(NSAIDs)和COX-2抑制剂抑制其活性可抑制结直肠癌的发展。然而，由于长期使用NSAIDs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则抑制结直肠肿瘤的发生。因此，为了防止结直肠癌的发生，重要的是要找到抑制COX-2和5-LOX的方法，并以最小的副作用刺激15-LOX。糖皮质激素(GCs)是最有效的内源性COX-2抑制剂，其作用受2型11ss-羟基类固醇脱氢酶(11ss-HSD2)下调，使GCs失活。GCS也抑制5-LOX途径，但刺激15-LOX途径。11ssHSD2主要在典型的醛固酮敏感上皮细胞中表达，如肾脏和结肠，但也在小肠中表达。11ssHSD2的升高与肿瘤的发生有关。我们发现11ssHSD2抑制可抑制肾皮质COX-2的表达。我们推测，抑制11ssHSD2将抑制COX-2和5-LOX途径，但通过提高肿瘤细胞内活性GC水平来刺激15-LOX途径，从而减少结直肠肿瘤的发生。本研究的目的有三个：目的1研究11ssHSD2抑制对小鼠肠息肉病(Min小鼠)模型的预防和治疗作用，以及11ssHSD2抑制对CT26肿瘤转移的预防作用；目的2研究11ssHSD2调控结直肠癌发生的机制；目的3研究5-LOX、15-LOX和COX-2通路在11ssHSD2抑制抑制腺瘤发生中的相对重要性。目前这一提议的完成可能为结直肠癌的化学预防和化疗指明新的策略，因为以下优点：1.甘草酸(GA)是一种含于甘草中的化合物，是一种强大的11ssHSD2抑制剂，无毒；由于其表达受限，抑制11ssHSD2被预测可以抑制CRC的发展，而不会因为长期使用COX-2抑制剂而带来潜在的心血管风险；3)GCS抑制COX-2的表达，但不抑制COX-1的表达。因此，抑制11ssHSD2可以抑制结直肠癌的发生，而不会产生NSAIDs抑制COX-1的潜在副作用；4)11ssHSD2抑制介导的细胞内GC升高也可能通过抑制5-LOX途径和刺激15-LOX途径来抑制结直肠癌的发生。公共卫生相关性：项目描述：尽管非类固醇抗炎药或选择性COX-2抑制剂抑制COX-2衍生的PGE2生物合成抑制结直肠肿瘤的发生，但由于长期使用非类固醇抗炎药和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。糖皮质激素是最有效的内源性COX-2抑制剂，其作用受2型11ss-羟基类固醇脱氢酶下调。在目前的方案中，我们将测试抑制2型11ss-羟基类固醇脱氢酶活性是否可以为结直肠癌的化学预防和化疗提供一种新的策略，副作用最小。