肿瘤缺氧微环境新调节因子在肿瘤治疗抵抗中的作用及其机制

Hypoxia is one of physical microenvironments of solid tumors during the progression of the tumors and induces resistance to chemo- and radiation therapy. However, the underlying mechanism remains to be elucidated. Our preliminary study indicated that HPIP, a gene with oncogenic characteristics, interacted with HIF-1α, Ras and BCRP, the important regulators of the hypoxic tumor microenvironment and inducers of cancer therapy resistance, and promoted the expression of HIF-1α and BCRP. The preliminary functional study revealed that HPIP conferred resistance to chemotherapeutic drugs and ionizing radiation. These results suggest that HPIP, as a novel regulator of the hypoxic tumor microenvironment, plays a role in cancer therapy resistance. In this study, based on these observations, we will further determine the role of HPIP in hypoxic tumor microenvironment-mediated resistance to chemo- and radiation therapy, using cultured cancer cells, animals and clinical specimen. We will elucidate the mechanisms by which HPIP induces hypoxic tumor microenvironment-mediated resistance to chemo- and radiation therapy via HIF-1α, Ras and BCRP using techniques such as protein-protein interaction and chromatin immunoprecipitation. We will also investigate the role of upstream factors of HPIP in regulation of the hypoxic tumor microenvironment and resistance to chemo- and radiation therapy. This study will further elucidate the relationship between the hypoxic tumor microenvironment and cancer therapy resistance and provide candidate target for development of novel drugs against cancer.

缺氧微环境是实体肿瘤发展过程中的普遍现象，可导致肿瘤对化疗和放疗的耐受，但调节这一过程的机制还有待阐明。我们的初步研究结果表明，具有癌基因特征的HPIP与肿瘤缺氧微环境和肿瘤治疗抵抗中起重要作用的调节因子HIF-1α、Ras、BCRP存在相互作用，并能促进HIF-1α和BCRP基因的表达；初步的功能实验表明HPIP与化疗药和辐射耐受相关，提示HPIP作为肿瘤缺氧微环境新的调节因子在肿瘤治疗抵抗中起作用。本研究拟在此基础上，在细胞、动物、临床标本中进一步确立HPIP在肿瘤缺氧微环境介导的放化疗抵抗中的作用，利用蛋白质间相互作用技术、ChIP等阐明HPIP通过HIF-1α、Ras、BCRP调节肿瘤缺氧微环境介导的放化疗抵抗的分子机制，确定HPIP在肿瘤缺氧微环境中的上游调节因子及其在肿瘤放化疗抵抗中的作用，为深入理解肿瘤缺氧微环境在肿瘤治疗抵抗中的作用及开发新的抗肿瘤药物提供依据和靶标

实体肿瘤内存在缺氧微环境是实体肿瘤发展过程中的普遍现象，缺氧微环境也是实体肿瘤微环境中的重要特征之一。肿瘤缺氧微环境进一步加剧了肿瘤细胞基因组不稳定性，并激活一些肿瘤生存因子, 导致肿瘤对化疗和放疗的耐受，是肿瘤不良预后的指标。因此，对肿瘤缺氧微环境分子机制的阐明，不但有助于揭示肿瘤发生发展规律，而且将为肿瘤的诊断和治疗提供重要的理论依据和分子靶标。本项目发现HPIP（hematopoietic PBX-interacting protein）是一新的肿瘤缺氧微环境的调节因子，并与肿瘤放化疗抵抗相关。从细胞、动物、临床标本水平确定了HPIP在肿瘤缺氧微环境中的作用及其临床意义；阐明了HPIP在肿瘤缺氧微环境中调节肿瘤细胞生长及其放化疗抵抗的分子机制，即HPIP与多种缺氧调节因子（如Ras、BCRP、HIF1α、LEF1）在物理上和功能上存在相互作用，HPIP调节Ras-ERK信号通路，促进HIF-1α和BCRP基因的表达，增强LEF1转录活性；确定了HPIP的上游调控因子SIX1和microRNA-4310（miR-4310），SIX1和miR-4310分别通过正向和负向调控HPIP表达及其功能。SIX1是一个新的调控肿瘤有氧糖酵解（Warburg效应）的关键转录因子，可被缺氧诱导，能结合到糖酵解通路中绝大多数基因的启动子上促进这些基因的转录和表达，从而促进肿瘤生长。这些研究结果为深入理解肿瘤缺氧微环境在肿瘤治疗抵抗中的作用及开发新的抗肿瘤药物提供了理论依据和候选靶标。