STAT3通路调控EZH2磷酸化介导头颈部鳞状细胞癌乏氧耐受的机制研究

STAT3和HIF-1α异常激活及核定位是头颈部鳞癌(HNSCC)乏氧耐受的驱动力量。我们前期发现，HNSCC侵袭前锋EZH2高表达和胞浆聚集、HIF-1α异常赖氨酸甲基化修饰与EZH2共定位;STAT3促进EZH2磷酸化和胞浆转位。据此，我们提出“STAT3通路调控EZH2磷酸化介导HNSCC乏氧耐受”的科学假说。本项目拟研究:HNSCC中HIF-1α/STAT3/EZH2表达特征与乏氧程度关系；证明STAT3转录激活HIF-1基因;明确STAT3促进EZH2胞浆转位的关键磷酸化位点；阐明胞浆EZH2调控HIF-1α赖氨酸甲基化修饰及核转位机制；体内外实验研究STAT3/EZH2轴调控肿瘤血管新生和侵袭介导乏氧耐受。预期结果将从转录及翻译后修饰的角度阐述STAT3双重调控HIF-1α影响HNSCC乏氧耐受的机制，为开发以STAT3/EZH2为核心的联合治疗策略提供实验依据和理论基础。

Abnormal activation and nuclear accumulation of STAT3 and HIF-1α was the drive force of hypoxia tolerance in HNSCC. Our preliminary study indicated that EZH2 was highly expressed in invasive front and accumulated in cytoplasm in HNSCC tumor samples. HIF-1α was methylated at Lysine abnormally and co-localized with EZH2. STAT3 triggered phosphorylation and cytoplasm accumulation of EZH2. Thus, we propose the research hypothesis that STAT3 signaling regulates hypoxia tolerance via EZH2 phosphorylation in HNSCC. In the current research program, we will study as follows: the expression character of HIF-1α/STAT3/EZH2 in HNSCC and its correlation with hypoxia status. We will employ several HNSCC cell lines and in vivo tumor models to study: the mechanism that STAT3 triggers HIF-1 transcription; STAT3 promotes EZH2 phosphorylation and subcellular accumulation.STAT3/EZH2 activation triggers cancer cell hypoxia tolerance through invasiveness and angiogenesis. Expected research results will elucidate that STAT3 triggers HIF-1 transcription and regulating HIF-1α methylation in HNSCC hypoxia tolerance. We will also provide experimental evidence and theoretical basis for novel combined therapy based on targeting STAT3/EZH2 axis in HNSCC.