Role of Claudin-1 in Colon Cancer

Claudin-1 在结肠癌中的作用

• 批准号: 8803365
• 负责人: PUNITA DHAWAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803365
• 关键词: Affect; Americas; Antineoplastic Agents; Cancer Etiology; Cause of Death; Cell Count; Cell Differentiation process; Cessation of life; Clinical Management; Colitis; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Development; Diagnosis; Disease; Disease Progression; Effectiveness; Equilibrium; Excision; Female; Goals; Goblet Cells; Growth; Health; Homeostasis; Immune; Incidence; Inflammation; Intestines; Investigation; Laboratories; Malignant Neoplasms; Mediating; Military Personnel; Mission; Molecular; Morbidity - disease rate; Mucositis; Mus; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Population; Predisposition; Process; Proteins; Quality of life; Regulation; Rest; Role; Signal Transduction; Sodium Dextran Sulfate; Staging; Testing; Therapeutic Intervention; Tight Junctions; Toxic effect; Transcriptional Regulation; Transgenic Mice; Tumor Burden; United States; Veterans; Western World; Work; cancer cell; cancer stem cell; chemotherapy; claudin-1 protein; colon cancer patients; colon carcinogenesis; colon tumorigenesis; disease diagnosis; immune activation; improved; inhibitor/antagonist; interest; male; mortality; mouse model; notch protein; novel; novel strategies; novel therapeutics; offspring; overexpression; prevent; protein expression; screening; stem cell population; therapy development; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the Veterans armed forces personnel and each year Veterans affairs manages and treats ~175,000 colorectal cancer patients [1]. Although, significant advances are made in the screening/diagnosis of the disease, treatment options remain only moderately successful and primarily include surgical resection and chemotherapy. Importantly, disease progression and metastasis remain the prime cause of the morbidity and mortality among VA-CRC patients. Thus, new therapies with the promise to inhibit CRC progression are urgently needed. Our studies are an important step in that direction. Notably, extensive work from our and other laboratories has confirmed that expression of claudin-1 is highly upregulated in CRC in a stage-specific manner, and is causally associated with CRC growth and progression. Now, using a novel mouse model of intestine-specific claudin-1 overexpression, we show novel role of claudin-1 in the regulation of Notch-signaling and colonocyte maturation/goblet cell differentiation/Muc-2 expression. We further demonstrate multi-fold increase in colonic tumor burden (tumor incidence and growth) and aggressiveness in the offspring generated through the cross between APCmin and claudin-1 transgenic mice. In our continued study, we have now generated evidence that Notch- and Wnt-signaling synergize in claudin-1-dependent manner to augment CRC in APCmin/Cl-1 mice, possibly through the regulation of cancer stem cells. Taken together, our hypothesis is that increased claudin-1 expression induces Notch-hyper activation to dysregulate normal colonic differentiation and homeostasis, and thus induces susceptibility to CRC growth & progression through the synergy between Notch and Wnt- signaling. To test our hypothesis, we propose following specific aims: Specific Aim 1. Determine that claudin-1 expression modulates Notch-signaling to regulate colon tumorigenesis. Here we will: a) determine that Notch-signaling regulates increased tumorigenesis in APCmin/Cl-1 mice; b) determine whether mucosal inflammation contributes to Claudin-1-dependent increase in colon tumorigenesis and/or aggressiveness; c) determine the mechanism/s underlying Claudin-1-dependent regulation of Notch-activation. Specific Aim 2. To determine that Notch synergizes with Wnt/b-catenin signaling to regulate claudin-1- dependent increase in colon tumorigenesis. Here, we will determine: a) the impact of inhibition of Wnt/b- catenin-signaling on colon tumorigenesis in APCmin/Cl-1 mice.; b) that claudin-1-dependent increase in Wnt/b- catenin signaling depends upon Notch-activation and to examine the underlying mechanism/s; c) whether claudin-1 expression correlates with Notch and b-catenin/Wnt-activation in colon cancer patients and its potential association with the aggressiveness of cancer. Specific Aim 3. To investigate the role of APC/ Wnt-signaling in the regulation of colonic Claudin-1 expression. Here, we will: a) examine the role of APC (WT)-Smad4 axis in the regulation of Claudin-1 expression; b) determine the details of the cross-talk between APC and Smad4 in transcriptional regulation of Claudin-1. Our short term goal is to better understand how dysregulation of claudin-1 expression modulates the ability of colon cancer cells to form tumor and further progression. Our long term goal is to develop claudin-1-specific inhibitors that can be delivered specifically to the colon cancer cells and thus to create an anti-CRC drug that is not toxic and inhibits disease progression. We believe such therapeutic interventions can significantly increase survival and quality of life US Veterans who are suffering from colorectal cancer.

描述（由申请人提供）： 结直肠癌 (CRC) 是退伍军人武装部队人员癌症相关死亡的主要原因之一，退伍军人事务部每年管理和治疗约 175,000 名结直肠癌患者 [1]。尽管在疾病的筛查/诊断方面取得了重大进展，但治疗方案仍然只取得了一定的成功，主要包括手术切除和化疗。重要的是，疾病进展和转移仍然是 VA-CRC 患者发病和死亡的主要原因。因此，迫切需要有望抑制 CRC 进展的新疗法。我们的研究是朝这个方向迈出的重要一步。值得注意的是，我们和其他实验室的大量工作已经证实，claudin-1 的表达在 CRC 中以特定阶段的方式高度上调，并且与 CRC 的生长和进展存在因果关系。现在，利用肠道特异性claudin-1过表达的新型小鼠模型，我们展示了claudin-1在Notch信号传导和结肠细胞成熟/杯状细胞分化/Muc-2表达调节中的新作用。我们进一步证明，通过 APCmin 和claudin-1 转基因小鼠杂交产生的后代，结肠肿瘤负荷（肿瘤发生率和生长）和攻击性增加了数倍。在我们的持续研究中，我们现已获得证据表明，Notch 和 Wnt 信号传导以claudin-1依赖性方式协同作用，从而增强 APCmin/Cl-1 小鼠的 CRC，可能是通过癌症干细胞的调节。综上所述，我们的假设是，claudin-1 表达增加会诱导 Notch 过度激活，从而失调正常结肠分化和稳态，从而通过 Notch 和 Wnt 信号传导之间的协同作用诱导 CRC 生长和进展的易感性。为了检验我们的假设，我们提出以下具体目标： 具体目标 1.确定claudin-1表达调节Notch信号传导以调节结肠肿瘤发生。在这里，我们将： a) 确定 Notch 信号传导调节 APCmin/Cl-1 小鼠中肿瘤发生的增加； b) 确定粘膜炎症是否导致 Claudin-1 依赖性结肠肿瘤发生和/或侵袭性增加； c) 确定Notch激活的Claudin-1依赖性调节的潜在机制。具体目标 2. 确定 Notch 与 Wnt/b-catenin 信号传导协同作用，调节 Claudin-1 依赖性结肠肿瘤发生的增加。在这里，我们将确定：a) 抑制 Wnt/b-连环蛋白信号传导对 APCmin/Cl-1 小鼠结肠肿瘤发生的影响。 b) Wnt/b-连环蛋白信号传导中claudin-1依赖性增加取决于Notch激活并检查潜在机制； c) 结肠癌患者中claudin-1的表达是否与Notch和b-连环蛋白/Wnt激活相关，及其与癌症侵袭性的潜在关联。具体目标3.研究APC/Wnt信号传导在结肠Claudin-1表达调节中的作用。在这里，我们将： a) 检查 APC (WT)-Smad4 轴在 Claudin-1 表达调节中的作用； b) 确定 APC 和 Smad4 在 Claudin-1 转录调控中的串扰细节。我们的短期目标是更好地了解claudin-1表达失调如何调节结肠癌细胞形成肿瘤和进一步进展的能力。我们的长期目标是开发能够特异性递送至结肠癌细胞的claudin-1特异性抑制剂，从而创造出一种无毒且抑制疾病进展的抗CRC药物。我们相信，此类治疗干预措施可以显着提高患有结直肠癌的美国退伍军人的生存率和生活质量。