HDAC1/EGR1/miR-92b生物轴调控食管癌浸润转移的机制研究

Invasion and metastasis are major contributors to cancer-caused death in patients suffered from esophageal squamous cell carcinoma (ESCC), which needs more attention to explore the underlying mechanism involved further. On the basis of chemotaxis selection model in vitro, we found that miR-92b, whose expression correlates inversely with lymph node metastasis and indicated better prognosis, could dramatically impede invasion and metastasis of ESCC cells in vitro and in vivo. However, the underlying mechanism of regulating its expression remains unclear. According to the expression profiling, transcriptional factor EGR1 was found to dramatically inhibit the migration and invasion of ESCC cells. Thus, we proposed the hypothesis that HDAC1/EGR1/miR-92b axis regulates invasion-metastasis cascade of esophageal cancer. In this research program, we aim to identify the relationship between HDAC1/EGR1 expression and lymph node metastasis as well as prognosis, reveal the mechanism that HDAC1 regulates EGR1 dually to affect the transcription of miR-92b, and explore the function of HDAC1/EGR1/miR-92b in vitro and in vivo. Expected research results will elucidate the function and mechanism of HDAC1/EGR1/miR-92b axis in ESCC local invasion and metastasis, and provide new insight into clinical molecular diagnosis and anti-cancer strategies.

食管癌发生浸润转移是导致不良预后的重要原因之一，其调控机制亟待深入研究。我们前期利用chemotaxis模型发现miR-92b能够显著抑制食管癌的浸润转移，且表达与淋巴结转移负相关，但调控其表达的分子机制尚不明确。通过表达谱芯片筛选，我们发现EGR1能够抑制食管癌细胞的运动和浸润，并提出了“HDAC1/EGR1/miR-92b生物轴调控食管癌的浸润转移”的研究假说。本项目拟在食管癌标本中研究HDAC1和EGR1的表达及与淋巴结转移及预后的关系；通过双荧光素酶报告基因和ChIP实验证明HDAC1通过双重调控EGR1从而影响miR-92b转录的机制；在体外功能实验和动物浸润转移模型中探究HDAC1/EGR1/miR-92b生物轴对食管癌浸润转移的影响。预期研究结果将揭示HDAC1/EGR1/miR-92b生物轴调控食管癌浸润转移的分子机制，为食管癌的临床诊断和治疗提供新的思路。

食管鳞癌发生浸润转移是导致不良预后的重要原因之一，其调控机制亟待深入研究。我们前期基于chemotaxis模型进行了表达谱芯片筛选，发现EGR1在运动能力较强的细胞亚型中表达显著下降，但其在食管鳞癌中的功能和机制尚不明确。本项目旨在鉴定EGR1在食管鳞癌组织中的表达水平；通过RNAseq及ChIPseq等实验阐明EGR1的调控机制；在体外功能实验和动物转移模型中证实EGR1对食管鳞癌浸润转移的影响。结果表明在组蛋白去乙酰化酶的表观调控下，EGR1在食管鳞癌中显著低表达；进一步研究显示EGR1能够转录激活HOMER2从而抑制食管鳞癌的浸润转移。本项目揭示了EGR1抑制食管鳞癌浸润转移的作用机制，为食管鳞癌的临床诊断和治疗提供了潜在靶点。