cZNF292/SOX9/β-catenin信号通路对乏氧肿瘤细胞放射敏感性的调控作用及其机制

Hypoxia is common in solid tumors. Improving the radiosensitivity of hypoxia tumor cells is an important way to improve the effect of radiotherapy. Our previous studies have found that hypoxia induced the expression of Circular RNA ZNF292 (cZNF292) in hepatocellular carcinoma cells. The cZNF292 distributed in cytoplasm combined wtth SOX9 protein and inhibited its nuclear translocation, resulting in the enhancement of Wnt/β-catenin pathway activity. The silencing of cZNF292 significantly decreased the activity of Wnt/β-catenin pathway and inhibited the proliferation, vasculogenic mimicry (VM) and radiation resistance of hypoxic HCC cells. Therefore, it is presumed that the cZNF292/SOX9/β-catenin signaling pathway may be a new important pathway for regulating the proliferation, VM and radiosensitivity of hypoxic tumor cells. In the present study, the effect of cZNF292, SOX9 and β-catenin over-expression and knockdown on hypoxic tumor cells radiosensitivity and its molecular mechanism will be investigated. The feasibility of targeting cZNF292/SOX9/β-catenin passway to improve the efficacy of solid tumor radiotherapy will be assessed through orthotopic transplanted tumor model in nude mice.

乏氧在实体瘤中普遍存在，提高乏氧肿瘤细胞的放射敏感性是提高放疗效果的重要途径。我们的前期研究发现，乏氧诱导肝癌细胞Circular RNA ZNF292 (cZNF292)表达增强，分布于胞浆的cZNF292结合SOX9蛋白，抑制其核转位，导致Wnt/β-catenin通路活性增强。而沉默cZNF292明显降低Wnt/β-catenin通路活性，抑制乏氧肝癌细胞增殖、血管生成拟态（VM）和放射抗性。因此推测cZNF292/SOX9/β-catenin信号通路可能是调控乏氧肿瘤细胞增殖、VM和放射敏感性的新的重要通路。本研究拟探讨过表达和敲低cZNF292、SOX9和β-catenin对乏氧肿瘤细胞放射敏感性的影响及其机制，并通过裸鼠体内原位移植瘤放疗效果分析，评估以cZNF292/SOX9/β-catenin信号通路为靶点提高实体瘤放疗疗效的可行性。

缺氧是肿瘤微环境的典型特征，并已被确定为调控放疗结果的关键表观遗传因素。环状RNA（circRNAs）是一种具有共价封闭环状结构的新型RNA分子，在真核转录体中高度表达。尽管先前的分析表明，circRNA ZNF292（cZNF292）是缺氧反应性的，并表现出促血管生成功能，但其生物学功能的分子机制尚不清楚，值得进一步探索。在本研究项目中，我们探究了cZNF292对缺氧肝癌SMMC7721细胞血管生成拟态（VM）和放射敏感性的影响及其机制。我们的数据表明，cZNF292在肝癌细胞中的乏氧诱导表达呈时间依赖性增强，且与缺氧诱导因子（HIF）-1α无关。cZNF292的敲除增加了SRY（性别决定区Y）-box9（SOX9）核易位，从而降低Wnt/β-catenin通路活性，导致缺氧肝癌细胞增殖的抑制，VM降低，以及辐射抗性下降。我们的结果揭示了cZNF292增强缺氧肿瘤细胞放射敏感性的新机制，这可能为肝癌的放射治疗提供有价值的靶点。