Role of claudin-1 in Colon Cancer

在疾病诊断时，结肠癌（CRC）分期对患者生存至关重要， 范围从90%的局部疾病患者到13%的 转移因此，提高了对CRC进展的分子调控的理解， 转移是关键和紧迫的，开发新的治疗方法。在这方面，我们的研究， 和其他实验室，为上调的claudin的偶然作用提供了强有力的支持， 1的表达促进了CRC的恶性程度，尤其是转移。上调（和 在主要与CRC相关的CRC患者样品中的claudin-1表达 肝转移（58%），淋巴结转移（35%）。此外，基因操作claudin-1 表达足以在体外和体内调节CRC细胞系的转移能力。 进一步的分析表明，原癌基因Src和EphA 2在claudin-1中起着重要作用。 介导的CRC进展。本提案的主要目标是确定Src的作用， 和EphA 2-信号传导在失调的密蛋白条件下促进CRC恶性肿瘤中的作用。 1的表达，以及一种新型claudin-1抑制剂的临床前试验，以确定其在 抑制CRC恶性肿瘤。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表达失调如何促进结肠癌的扩散 细胞和转移;和特异性目的-2。为了测试新型抗claudin-1的治疗效果， 小分子抑制剂（I-6）抑制CRC恶性肿瘤。这项研究的结果是 预期对预防/抑制CRC转移具有实质性影响。

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.