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首页> 美国卫生研究院文献>Oncology Letters >Insulin-like growth factor-1 receptor knockdown enhances radiosensitivity via the HIF-1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells
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Insulin-like growth factor-1 receptor knockdown enhances radiosensitivity via the HIF-1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells

机译：胰岛素样生长因子-1受体敲低可通过HIF-1α途径增强放射敏感性并减弱人肺鳞状细胞癌细胞的ATM / H2AX / 53BP1 DNA修复激活

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Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor involved in cell proliferation and apoptosis, which is highly expressed in lung squamous cell carcinoma (SCC). The present study aimed to observe the influence of IGF-1R silencing on the radiosensitivity of SCC and investigate the potential mechanisms involved. Human lung SCC H520 cells with relatively high expression of IGF-1R were used. IGF-1R expression was silenced using short hairpin RNA. The influence of IGF-1R silencing on radiosensitivity and apoptosis was assessed using a clone formation assay and flow cytometry. The expression levels of proteins relevant in DNA damage repair and hypoxic signaling pathways were analyzed using western blotting. Decreased expression of IGF-1R led to an increase in the sensitivity of H520 cells to irradiation. Molecular analysis showed that the reduced expression of IGF-1R decreased the protein expression of ataxia-telangiectasia mutated (ATM), H2A histone family member X (H2AX) and p53 binding protein 1 (53BP1), which are associated with the DNA repair pathway. Furthermore, 53BP1 is also known to be involved in apoptosis. Proteins involved in the hypoxic pathway, including hypoxia inducible factor 1 α (HIF-1α), matrix metallopeptidase 9 (MMP-9) and vascular endothelial growth factor A (VEGFA) were also involved in the radiosensitivity. In conclusion, decreased expression of IGF-1R leads to improved radiosensitivity of SCC cells, and the underlying mechanism may be associated with the decreased expression of proteins involved in ATM/H2AX/53BP1 DNA damage repair and the HIF-1α/MMP-9 hypoxic pathway, which results in the induction of apoptosis and increased radiosensitivity. These findings suggest that targeting of IGF-1R may represent a novel approach for lung SCC radiation treatment.
机译：胰岛素样生长因子-1受体（IGF-1R）是一种参与细胞增殖和凋亡的细胞膜受体，在肺鳞状细胞癌（SCC）中高度表达。本研究旨在观察IGF-1R沉默对SCC放射敏感性的影响，并探讨其潜在的机制。使用了具有较高IGF-1R表达的人肺SCC H520细胞。使用短发夹RNA沉默IGF-1R表达。使用克隆形成试验和流式细胞术评估了IGF-1R沉默对放射敏感性和细胞凋亡的影响。使用蛋白质印迹分析与DNA损伤修复和缺氧信号通路相关的蛋白质的表达水平。 IGF-1R的表达减少导致H520细胞对辐射的敏感性增加。分子分析表明，IGF-1R的减少表达降低了共济失调毛细血管扩张突变（ATM），H2A组蛋白家族成员X（H2AX）和p53结合蛋白1（53BP1）的蛋白表达，这与DNA修复途径有关。此外，还已知53BP1与细胞凋亡有关。参与低氧途径的蛋白质，包括低氧诱导因子1α（HIF-1α），基质金属肽酶9（MMP-9）和血管内皮生长因子A（VEGFA）也参与了放射敏感性。总之，IGF-1R的表达降低导致SCC细胞放射敏感性提高，其潜在机制可能与参与ATM / H2AX / 53BP1 DNA损伤修复和HIF-1α/ MMP-9低氧的蛋白质表达降低有关。诱导凋亡并增加放射敏感性。这些发现表明，靶向IGF-1R可能代表一种用于肺SCC放射治疗的新方法。

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