PDF(Pubmed)
Abstract：
Esophageal squamous cell carcinoma (ESCC) is a deadly consequence of radiation exposure to the esophagus. ESCC arises from esophageal epithelial cells that undergo malignant transformation and features a perturbed squamous cell differentiation program. Understanding the dose- and radiation quality-dependence of the esophageal epithelium response to radiation may provide insights into the ability of radiation to promote ESCC. We have explored factors that may play a role in esophageal epithelial radiosensitivity and their potential relationship to ESCC risk. We have utilized a murine three-dimensional (3D) organoid model that recapitulates the morphology and functions of the stratified squamous epithelium of the esophagus to study persistent dose- and radiation quality-dependent changes. Interestingly, although high-linear energy transfer (LET) Fe ion exposure induced a more intense and persistent alteration of squamous differentiation and 53BP1 DNA damage foci levels as compared to Cs, the MAPK/SAPK stress pathway signaling showed similar altered levels for most phospho-proteins with both radiation qualities. In addition, the lower dose of high-LET exposure also revealed nearly the same degree of morphological changes, even though only ~36% of the cells were predicted to be hit at the lower 0.1 Gy dose, suggesting that a bystander effect may be induced. Although p38 and ERK/MAPK revealed the highest levels following high-LET exposure, the findings reveal that even a low dose (0.1 Gy) of both radiation qualities can elicit a persistent stress signaling response that may critically impact the differentiation gradient of the esophageal epithelium, providing novel insights into the pathogenesis of radiation-induced esophageal injury and early stage esophageal carcinogenesis.
摘要：
食管鳞状细胞癌（ESCC）是食道辐射暴露的致命后果。ESCC产生于经历恶性转化并具有扰动的鳞状细胞分化程序的食管上皮细胞。了解食道上皮对辐射反应的剂量和辐射质量依赖性可以提供对辐射促进ESCC能力的见解。我们已经探索了可能在食管上皮放射敏感性中起作用的因素及其与ESCC风险的潜在关系。我们利用了鼠类三维（3D）类器官模型，该模型概括了食管分层鳞状上皮的形态和功能，以研究持续的剂量和辐射质量依赖性变化。有趣的是,尽管与Cs相比，高线性能量转移（LET）铁离子暴露引起鳞状细胞分化和53BP1DNA损伤灶水平的更强烈和持续的改变，MAPK/SAPK应激途径信号对大多数具有两种放射质量的磷酸蛋白显示相似的改变水平.此外,低剂量的高LET暴露也显示出几乎相同程度的形态学变化，即使只有约36％的细胞被预测在较低的0.1Gy剂量下被击中，这表明可能会引起旁观者效应。尽管p38和ERK/MAPK在高LET暴露后显示出最高水平，研究结果表明，即使两种辐射质量的低剂量（0.1Gy）也可以引起持续的应激反应，这可能严重影响食管上皮的分化梯度，为放射性食管损伤和早期食管癌的发病机制提供新的见解。
