BH3-only protein BNIP3 in tumor progression

描述(申请人提供)：BNIP3是一种仅BH3-BCL-2家族线粒体蛋白。BNIP3的过度表达导致线粒体功能障碍和缓慢的坏死型细胞死亡。Bnip3基因的表达在低氧微环境中被激活，是转录因子HIF-1的直接靶点。Bnip3的表达与乳腺和肺的高级别侵袭性肿瘤有关。我们的假设表明，在低氧和酸性的肿瘤微环境中，Bnip3的长期过度表达导致了侵袭性肿瘤细胞的进化。我们将在人肺和乳腺癌细胞系的小鼠异种移植模型中检验这一假设。我们的假设还预测，BNIP3诱导的线粒体功能障碍激活了线粒体逆行信号通路，从而激活了与肿瘤侵袭和生存相关的标志物的表达。我们建议确定BNIP3的表达对线粒体信号分子和效应核转录因子的影响。线粒体信号通路在BNIP-3诱导的肿瘤进展中的作用将由这些通路的显性负抑制物的使用来确定。我们提议的项目将支持一个新的概念，即在缺氧性实体肿瘤中慢性过表达促死亡分子可能导致肿瘤侵袭性和进展性的进化。我们的结果也可能为BNIP3可能成为人类癌症的一个新的预后标志物提供实验支持。

DESCRIPTION (provided by applicant): BNIP3 is a BH3-only BCL-2 family mitochondrial protein. Overexpression of BNIP3 causes mitochondrial dysfunction and a slow necrosis-type of cell death. The expression of the Bnip3 gene is activated in hypoxic microenvironments and is a direct target for the transcription factor HIF-1. Expression of Bnip3 is associated with high-grade invasive tumors of the breast and lung. Our hypothesis suggests that chronic overexpression of Bnip3 in a hypoxic and acidic tumor microenvironment results in the evolution of aggressive tumor cells. We will test this hypothesis in the mouse xenotransplant model of human lung and mammary carcinoma cell lines. Our hypothesis also predicts that BNIP3-induced mitochondrial dysfunction activates the retrograde mitochondrial signaling pathway resulting in activation of expression of markers associated with tumor invasion and survival. We propose to determine the effects of BNIP3 expression on mitochondrial signaling molecules and effector nuclear transcription factors. The role of the mitochondrial signaling pathway in BNIP-3-induced tumor progression will be determined by the use of dominant negative inhibitors of the pathways. Our proposed project will provide support for a new concept that chronic overexpression of a death-promoting molecule in hypoxic solid tumors may lead to the evolution of tumor aggressiveness and progression. Our results may also provide the experimental support to suggest that BNIP3 may be a new prognostic marker for human cancer.