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: 8242886
• 负责人: Mingzhi Zhang
• 金额: $ 31.4万
• 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/8242886
• 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; 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

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.

项目概要 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 癌症。 CRC 中环加氧酶 2 (COX-2) 表达增加，并通过抑制其活性 长期使用非甾体抗炎药 (NSAID) 和 COX-2 抑制剂可抑制 CRC 发展。然而，长期使用 NSAID 和 COX-2 抑制剂导致的副作用增加限制了 它们在结直肠癌化学预防和化疗中的潜在用途。近日，有人提出， 5-脂氧合酶 (5-LOX) 促进结直肠肿瘤发生，而 15-LOX 则抑制结直肠肿瘤发生。因此，要 为了预防 CRC 的发展，重要的是找到抑制 COX-2 和 5-LOX 并刺激的方法 15-LOX 副作用最小。糖皮质激素 (GC) 是最有效的内源性 COX-2 抑制剂，其作用被 2 型 11ss-羟基类固醇脱氢酶下调 (11ssHSD2)，使 GC 失活。 GC 还抑制 5-LOX 途径，但刺激 15-LOX 途径。 11ssHSD2 主要在经典醛固酮敏感上皮细胞中表达，例如 肾和结肠，但也在小肠中表达。 11ssHSD2 的升高与 肿瘤发生。我们发现 11ssHSD2 抑制可抑制肾皮质中 COX-2 的表达。 我们假设 11ssHSD2 抑制会抑制 COX-2 和 5-LOX 途径，但 通过提高肿瘤细胞内活性 GC 的水平来刺激 15-LOX 通路，并将 从而减少结直肠肿瘤的发生。我们在当前提案中有三​​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效果 肠息肉病（Min小鼠）及11ssHSD2抑制对CT26肿瘤的预防作用 转移;目标2将研究11ssHSD2调节结直肠肿瘤发生的机制；和 目标 3 将研究 11ssHSD2 中 5-LOX、15-LOX 和 COX-2 通路的相对重要性 抑制介导的腺瘤发展抑制。当前提案的完成可能表明 结直肠癌化学预防和化疗的新策略具有以下优点： 1. 甘草酸 (GA) 是甘草中含有的一种化合物，是一种强大的 11ssHSD2 抑制剂， 无毒； 2）。由于其表达受限，预计抑制 11ssHSD2 会抑制 CRC 开发过程中不存在长期使用 COX-2 抑制剂带来的潜在心血管风险； 3）。 GC 抑制 COX-2 的表达，但不抑制 COX-1 的表达。因此，抑制 11ssHSD2 将抑制 CRC 开发过程中不会因 NSAIDs 抑制 COX-1 而产生潜在副作用； 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肿瘤的发生： 抑制 5-LOX 途径并刺激 15-LOX 途径。