Role of claudin-1 in Colon Cancer

Claudin-1 在结肠癌中的作用

• 批准号: 10049181
• 负责人: PUNITA DHAWAN
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049181
• 关键词: Adenocarcinoma; Adjuvant; Affect; Americas; Anoikis; Apoptosis; Cancer Patient; Cell Culture Techniques; Cells; Cessation of life; Chemoresistance; Clinical Management; Clinical Research; Coin; Colon Carcinoma; Colorectal Cancer; Data; Diagnosis; Diagnostic Neoplasm Staging; Disease Management; Disseminated Malignant Neoplasm; Drug Kinetics; Female; Fluorouracil; Fostering; General Population; Human; In Vitro; Incidence; Investigation; LGR5 gene; Laboratories; Lead; Localized Disease; Maintenance; Malignant Neoplasms; Mediating; Metabolism; Metastatic Neoplasm to the Liver; Modeling; Molecular; Multiprotein Complexes; Mus; Neoplasm Metastasis; Outcome; Outcome Study; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Population; Preclinical Testing; Prevention; Process; Proteins; Proto-Oncogenes; Publishing; Regulation; Resistance; Role; Sampling; Signal Transduction; Testing; Tight Junctions; Time; Toxic effect; Transgenic Mice; Treatment Efficacy; United States; United States Department of Veterans Affairs; Veterans; Work; adenoma; cancer cell; cancer stem cell; cancer therapy; claudin-1 protein; clinical efficacy; cohort; colon cancer cell line; colon cancer metastasis; colon cancer patients; colon cancer prevention; colon cancer progression; colon cancer treatment; disease diagnosis; follow-up; genetic manipulation; improved; in vivo; inhibitor/antagonist; lymph nodes; male; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; oxaliplatin; patient population; preclinical study; prognostic significance; small molecule inhibitor; stem cell biomarkers; stem cell population; targeted treatment; therapeutic evaluation; therapeutic target; therapy resistant; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenic; v-src Oncogenes; villin

The colon cancer (CRC) staging, at the time of disease diagnosis, is critical for patient survival, which ranges from 90% for patients with localized disease to meagre 13% for the ones with metastasis. Thus, improved understanding of the molecular regulation of CRC-progression and metastasis is critical and urgent, to develop novel therapies. In this regard, studies from our, and other laboratories, have provided strong support for a casual role for upregulated claudin- 1 expression in promoting CRC malignancy, especially metastasis. An upregulated (and mislocalized) claudin-1 expression in CRC patient samples associated predominantly with CRC metastasis to liver (58%) and lymph nodes (35%). Moreover, genetic manipulation of claudin-1 expression was sufficient to modulate metastatic ability of CRC cells lines in vitro and in vivo. Further analysis suggested essential roles of proto-oncogenes Src and EphA2 in claudin-1 mediated CRC progression. The key objectives of this proposal are to determine the roles of Src- and EphA2-signaling in fostering CRC malignancy under conditions of the dysregulated claudin- 1 expression, and preclinical testing of a novel claudin-1 inhibitor for its therapeutic efficacy in inhibiting CRC malignancy. To test our hypothesis we propose following studies: Specific Aim- 1. To determine how dysregulated claudin-1 expression promotes dissemination of colon cancer cell and metastasis; and Specific Aim-2. To test therapeutic efficacy of a novel anti-claudin-1 small molecule inhibitor (I-6) in inhibiting CRC malignancy. The outcome of this study are expected to have substantial impact on prevention/inhibition of CRC metastasis.

结肠癌（CRC）分期在疾病诊断时对患者生存至关重要， 局部疾病患者的90％到有13％的患者 转移。因此，对CRC产生和 转移是至关重要的，紧急的，可以开发新的疗法。在这方面，我们的研究 和其他实验室，为上调的claudin- 1在促进CRC恶性肿瘤，尤其是转移中的表达。上调（和 CRC患者样品中的Claudin-1表达错误，主要与CRC相关 转移到肝脏（58％）和淋巴结（35％）。此外，Claudin-1的基因操纵 表达足以调节CRC细胞在体外和体内的转移能力。 进一步的分析表明，原始基因SRC和EPHA2在Claudin-1中的重要作用 介导的CRC进展。该提案的关键目标是确定SRC-的作用 在不调节的Claudin-的条件下，在促进CRC恶性肿的促进CRC恶性肿瘤中的EPHA2信号 1个表达和新型Claudin-1抑制剂的临床前测试其治疗功效 抑制CRC恶性肿瘤。为了检验我们的假设，我们提出以下研究：特定目的 - 1。确定claudin-1表达失调如何促进结肠癌的传播 细胞和转移；和特定的AIM-2。测试一种新型抗Claudin-1的治疗功效 小分子抑制剂（I-6）抑制CRC恶性肿瘤。这项研究的结果是 预计将对预防/抑制CRC转移产生重大影响。