Role of claudin-1 in Colon Cancer

在疾病诊断时，结肠癌(CRC)的分期对患者的生存至关重要， 从局部疾病患者的90%到患有局部疾病的患者的13%不等 转移。因此，提高了对结直肠癌进展和分子调控的理解 转移是关键和紧迫的，需要开发新的治疗方法。在这方面，我们的研究， 和其他实验室，为上调克拉丁的临时作用提供了强有力的支持- 1在促进结直肠癌恶性，尤其是转移中的表达。一个上调的(和 错误定位)Claudin-1在主要与结直肠癌相关的结直肠癌患者样本中的表达 肝转移(58%)和淋巴结转移(35%)。此外，claudin-1的基因操作 在体外和体内的表达足以调节结直肠癌细胞系的转移能力。 进一步分析提示原癌基因Src和EphA2在claudin-1中的重要作用 介导的CRC进展。这项建议的主要目标是确定资源中心的作用- 和EphA2信号转导在克拉丁异常调节条件下促进结直肠癌发生的作用 一种新的Claudin-1抑制剂的表达和临床前试验 抑制结直肠癌的恶性。为了验证我们的假设，我们提出了以下研究：具体目标-- 1.确定claudin-1表达异常如何促进结肠癌的扩散 细胞和转移；以及特异性靶点-2。检测一种新型抗Claudin-1药物的疗效 小分子抑制物(I-6)抑制结直肠癌恶性进展。这项研究的结果是 预计将对预防/抑制结直肠癌转移产生重大影响。

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.