Kumar Kamendra, Kumar Santosh, Angdisen Jerry, Datta Kamal, Fornace Albert J, Suman Shubhankar
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA.
Curr Oncol. 2025 Jul 1;32(7):382. doi: 10.3390/curroncol32070382.
Exposure to high-linear energy transfer (LET) heavy ions, such as Si, poses a significant cancer risk for astronauts. While previous studies have linked high-LET radiation exposure to persistent oxidative stress and dysregulated stress responses in intestinal crypt cells with an increased risk of tumorigenesis, the relationship between IR-induced oxidative DNA damage and intestinal cancer risk remains incompletely understood. Here, we investigated the time-dependent effects of Si-ion radiation on intestinal tumorigenesis and oxidative DNA damage in mice, a model for human intestinal cancer predisposition. Male mice were exposed to 10 cGy of either γ-rays (low-LET) or Si-ions (high-LET), and intestinal tumor burden was assessed at 60 and 150 days post-irradiation. While both radiation groups showed modest, non-significant tumor increases at 60 days, Si-irradiated mice exhibited an approximately 2.5-fold increase in tumor incidence by 150 days, with a higher incidence of invasive carcinomas compared to γ and sham groups. Serum 8-OxodG levels, a marker of systemic oxidative stress, were significantly elevated in the Si-ion group, correlating with increased intestinal 8-OxodG staining. Additionally, assessment of the proliferation marker Cyclin D1 and metaplasia marker Guanylyl Cyclase C (GUCY2C) also revealed significant crypt cell hyperproliferation accompanied by increased metaplasia in Si-exposed mouse intestines. Positive correlations between serum 8-OxodG and tumor-associated endpoints provide compelling evidence that exposure to Si-ions induces progressive intestinal tumorigenesis through sustained oxidative DNA damage, crypt cell hyperproliferation, and metaplastic transformation. This study provides evidence in support of the radiation quality-dependent progressive increase in systemic and intestinal levels of 8-OxodG during intestinal carcinogenesis. Moreover, the progressive increase in oxidative DNA damage and simultaneous increase in oncogenic events after Si exposure also suggest that non-targeted effects might be a significant player in space radiation-induced intestinal cancer development. The correlation between serum 8-OxodG and oncogenic endpoints supports its potential utility as a predictive biomarker of high-LET IR-induced intestinal carcinogenesis, with implications for astronaut health risk monitoring during long-duration space missions.
暴露于高传能线密度（LET）的重离子，如硅离子，对宇航员构成了重大的癌症风险。虽然先前的研究已将高LET辐射暴露与肠道隐窝细胞中持续的氧化应激和失调的应激反应联系起来，且肿瘤发生风险增加，但电离辐射（IR）诱导的氧化性DNA损伤与肠道癌症风险之间的关系仍未完全明了。在此，我们研究了硅离子辐射对小鼠肠道肿瘤发生和氧化性DNA损伤的时间依赖性影响，小鼠是人类肠道癌易感性的模型。雄性小鼠接受10厘戈瑞的γ射线（低LET）或硅离子（高LET）照射，并在照射后60天和150天评估肠道肿瘤负担。虽然两个辐射组在60天时肿瘤均有适度增加，但无统计学意义，而到150天时，硅离子照射的小鼠肿瘤发生率增加了约2.5倍，与γ射线照射组和假照射组相比，浸润性癌的发生率更高。血清8-氧代脱氧鸟苷（8-OxodG）水平是全身氧化应激的标志物，在硅离子组中显著升高，与肠道8-OxodG染色增加相关。此外，对增殖标志物细胞周期蛋白D1和化生标志物鸟苷酸环化酶C（GUCY2C）的评估还显示，在暴露于硅离子的小鼠肠道中，隐窝细胞显著过度增殖，同时化生增加。血清8-OxodG与肿瘤相关终点之间的正相关提供了有力证据，表明暴露于硅离子会通过持续的氧化性DNA损伤、隐窝细胞过度增殖和化生转化诱导渐进性肠道肿瘤发生。本研究为肠道致癌过程中全身和肠道8-OxodG水平随辐射质量而逐渐增加提供了证据支持。此外，硅离子暴露后氧化性DNA损伤的逐渐增加以及致癌事件的同时增加还表明，非靶向效应可能在太空辐射诱导的肠道癌症发展中起重要作用。血清8-OxodG与致癌终点之间的相关性支持其作为高LET IR诱导肠道致癌的预测生物标志物的潜在效用，这对长期太空任务期间宇航员健康风险监测具有重要意义。
