Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
Int J Biochem Cell Biol. 2019 Jun;111:12-18. doi: 10.1016/j.biocel.2018.09.013. Epub 2018 Sep 29.
Treatment failure through radioresistance of tumors is associated with activation of the epidermal growth factor receptor (EGFR). Tumor cell proliferation, DNA-repair, hypoxia and metastases-formation are four mechanisms in which EGFR signaling has an important role. However, the effect of hypoxia on EGFR expression is still controversial. In this study, we demonstrated that hypoxia enhanced EGFR expression and sustained cell survival in SiHa, CAL 27 and A549 cells at both low and high cell desnities, while in MCF-7, MDA-MB-231 and HeLa cells, EGFR and cell survival were regulated by hypoxic treatment in a cell-density dependent manner: upregulated at low cell density and downregulated at high cell density. In MCF-7 and HeLa xenografts in nude mice, EGFR expression varied inversely with the pimonidazole level that was used as an indicator of hypoxia, accordant with the effect of hypoxia at high cell density in vitro. Hypoxia induced more remarkable cell autophagy at high cell density than at low cell density. Autophagy inhibitor 3MA, rather than proteasome inhibitor MG132 inhibited hypoxia-mediated EGFR loss and shifted cell death to cell survival in HeLa cells. The MCF7 cells' sensitivity to ionizing radiation (IR) under hypoxia was also conditional on the cell densities when the hypoxia treatment was introduced, inversely associated with the expression levels of EGFR. Altogether, hypoxia can decrease EGFR expression in some cell lines by enhancing autophagy at high cell density, leading to cell death and hypersensitivity to radiotherapy. This study may help to understand how hypoxia influences EGFR expression and radiosensitivity.
肿瘤的放射抵抗导致治疗失败与表皮生长因子受体 (EGFR) 的激活有关。肿瘤细胞增殖、DNA 修复、缺氧和转移形成是 EGFR 信号转导发挥重要作用的四个机制。然而，缺氧对 EGFR 表达的影响仍存在争议。在这项研究中，我们证明了在 SiHa、CAL 27 和 A549 细胞中，无论细胞密度高低，缺氧均增强 EGFR 表达并维持细胞存活，而在 MCF-7、MDA-MB-231 和 HeLa 细胞中，EGFR 和细胞存活受缺氧处理的调节呈细胞密度依赖性：低细胞密度时上调，高细胞密度时下调。在裸鼠 MCF-7 和 HeLa 异种移植瘤中，EGFR 表达与作为缺氧指标的 pimonidazole 水平呈负相关，与体外高细胞密度缺氧的作用一致。与低细胞密度相比，缺氧在高细胞密度下诱导更明显的细胞自噬。自噬抑制剂 3MA 而非蛋白酶体抑制剂 MG132 抑制了缺氧介导的 EGFR 丢失，并将 HeLa 细胞的细胞死亡转变为细胞存活。在缺氧条件下，MCF7 细胞对电离辐射 (IR) 的敏感性也取决于引入缺氧处理时的细胞密度，与 EGFR 的表达水平呈负相关。总之，在高细胞密度下，缺氧通过增强自噬可以降低某些细胞系中的 EGFR 表达，导致细胞死亡和对放疗的超敏反应。本研究可能有助于了解缺氧如何影响 EGFR 表达和放射敏感性。
