慢性应激对直结肠癌发生发展、以及化疗耐药的调控作用及其分子机制

Colorectal cancer (CRC) is a leading cause of cancer related death worldwide. Epidemiological studies have strongly suggested that chronic stress promotes colorectal tumorigenesis. However, the direct evidence that chronic stress promotes colorectal tumorigenesis in vivo is still lacking, and the underlying molecular mechanisms are unclear. As a key tumor suppressor, p53 regulates various cellular responses, including apoptosis and cell cycle arrest, to prevent tumorigenesis. Loss or attenuation of p53 function greatly promotes colorectal tumorigenesis. Approximately 50% of CRC contain p53 mutation. p53 is also critical for effective chemotherapeutic response of CRC; loss of p53 promotes therapeutic resistance of CRC, which is mainly due to the impaired apoptotic response to therapeutic agents for CRC, such as 5-flurorouracil (5-FU) and cisplatin. Chronic restraint is a well-established mouse model that mimics chronic stress in humans by periodic immobilization of mice. Employing this model, we have investigated the effect of chronic restraint stress on tumorigenesis and response to 5-FU treatment in xenograft colorectal tumors formed by a pair of human CRC cell lines with or without p53 (HCT116 p53+/+ or p53-/- cells) in nude mice. Our preliminary results strongly suggest that chronic stress promotes the growth and chemoresistance of colorectal xenograft tumors, and the attenuation of p53 function is an important mechanism, which could be mediated by glucocorticoids elevated during chronic stress. However, in xenograft tumor models, the initiation, progression, and therapeutic response of tumors are greatly affected by properties of injected cancer cells in addition to the conditions of host mice. To establish the direct link between chronic stress and CRC in vivo, in this proposed study, we will investigate the effect of chronic stress on tumorigenesis and chemoresistance of CRC by employing Apc min/+ mice, a widely used mouse genetic model for human CRC study. Apc min/+ mice have one mutant allele of APC gene, a tumor suppressor involved in human CRC, and are prone to spontaneous intestinal and colorectal tumors. Furthermore, we will investigate the molecular mechanism by which chronic stress promotes colorectal tumorigenesis in mouse models. Particularly, we will investigate whether the elevated glucocorticoids during the chronic stress can reduce the function of p53, which in turn promotes colorectal tumorigenesis in mouse models. It’s our anticipation that this study will provide direct evidence from mouse models that chronic stress promotes tumorigenesis and therapeutic resistance of colorectal cancer, and furthermore, will reveal novel mechanism by which chronic stress promote colorectal tumorigenesis.

流行病学研究表明，慢性应激与大肠癌的发生发展及预后密切相关，但缺乏来自动物模型的直接实验证据支持，且相应分子机制不明。抑癌因子p53功能缺失或降低可显著促进大肠癌发生化疗耐药。通过模仿人慢性应激的慢性束缚小鼠模型和大肠癌裸鼠成瘤模型、以及这两种模型的组合，我们前期研究发现，糖皮质激素升高导致p53功能降低可能是介导慢性应激促进大肠癌发生发展、以及化疗耐药的关键分子事件。本项目拟通过慢性束缚模型联合Apc min/+小鼠原发大肠癌模型深入探讨慢性应激对大肠癌发生和化疗耐药的生物学效应，并阐明相应的分子机制，尤其是慢性应激和糖皮质激素调控p53功能的分子机制。本项目不仅能从原发大肠癌动物模型上为慢性应激促进大肠癌发生和化疗耐药提供直接实验证据，而且能为临床上通过干预慢性应激防治大肠癌的发生发展、以及改善大肠癌的化疗效果提供理论依据。

流行病学研究表明，慢性应激与大肠癌的发生发展及预后密切相关，但缺乏来自动物模型的直接实验证据支持，且相应分子机制不明。抑癌因子p53功能缺失或降低可显著促进大肠癌发生化疗耐药。通过模仿人慢性应激的慢性束缚小鼠模型和大肠癌裸鼠成瘤模型、以及这两种模型的组合，我们前期研究发现，糖皮质激素升高导致p53功能降低可能是介导慢性应激促进大肠癌发生发展、以及化疗耐药的关键分子事件。本项目拟通过慢性束缚模型联合Apc min/+小鼠原发大肠癌模型深入探讨慢性应激对大肠癌发生和化疗耐药的生物学效应，并阐明相应的分子机制，尤其是慢性应激和糖皮质激素调控p53功能的分子机制。本项目不仅能从原发大肠癌动物模型上为慢性应激促进大肠癌发生和化疗耐药提供直接实验证据，而且能为临床上通过干预慢性应激防治大肠癌的发生发展、以及改善大肠癌的化疗效果提供理论依据。