长链非编码RNA LOC100506403/HIF-1α正反馈通路调控低氧微环境下肿 瘤细胞和肿瘤相关巨噬细胞之间相互作用促进结直肠癌进展的机制研究

Hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role on metabolism reprogramming, angiogenesis and invasion of colorectal cancer (CRC), and serves both as a sensor and effector in responsive to tumor hypoxia. However, the related mechanisms are still undefined. Our preliminary study demonstrated that long non-coding RNA (lncRNA) LOC100506403 was a CRC-related and hypoxia-responsive lncRNA. Upregulated expression of LOC100506403 correlated with carcinogenesis and progression of CRC. LOC100506403/HIF-1α acted in a positive feed-back fashion and mediated the interaction between colon cancer cells and macrophages through transactivation of HIF-1α downstream targets, including GLUT1, LDHA, IL-1β, etc. Thus, we hypothesize that, LOC100506403/HIF-1α acts in a positive feed-back fashion in responsive to tumor hypoxia and mediate the interaction between cancer cells and macrophages through transactivation of HIF-1α downstream targets, resulting in CRC progression. We will further disclose the detail mechanisms and the clinicopathological relevance of LOC100506403/HIF-1α at different levels, including clinical specimens, in vitro experiments, cell and animal experiments. Therefore, this study will be hopeful to provide new understanding and strategy for prevention and treatment of CRC.

HIF-1α是肿瘤低氧环境下的关键信号分子，在结直肠癌 (CRC) 代谢重塑、血管生成、侵袭等过程中发挥重要作用，但相关机制仍然不明。我们初步发现长链非编码RNA (lncRNA) LOC100506403是CRC相关性及低氧反应性lncRNA，其表达与CRC进展呈正相关，并与HIF-1α存在正反馈调控现象，LOC100506403/HIF-1α通路通过转录激活GLUT1、LDHA、IL-1β等靶基因调控结肠癌细胞与巨噬细胞相互作用。因此提出假说：低氧条件下LOC100506403/HIF-1α通过正反馈调控机制，增强HIF-1α靶基因的转录激活，并以此调控肿瘤细胞与巨噬细胞之间的相互作用促进CRC的进展。我们拟于临床标本、体外实验、细胞及动物实验等层面进一步明确LOC100506403/HIF-1α正反馈通路的具体调控机制及其在CRC进展中的意义，以期为CRC防治提供新策略。

HIF-1α是肿瘤低氧环境下的关键信号分子，在结直肠癌 (CRC) 代谢重塑、血管生成、侵袭等过程中发挥重要作用，但相关机制仍然不明。本项目对LOC100506403/HIF-1α在低氧环境下对CRC发生发展的影响进行了研究，研究结果显示：1、验证了lncRNA LOC100506403是CRC相关性及低氧反应性lncRNA；2、LOC100506403与HIF-1α存在正反馈调控现象；3、LOC100506403/HIF-1α在细胞模型和动物实验模型中促进了CRC的进展；4、低氧条件下LOC100506403/HIF-1α增强HIF-1α靶基因的转录激活下游靶基因调控结肠癌细胞与巨噬细胞相互作用，促进了CRC的进展。本项目明确LOC100506403/HIF-1α正反馈通路的具体调控机制及其在CRC进展中的意义，为CRC防治提供新策略。