Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.
Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.
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DOI：
10.12688/f1000research.125272.2
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发表时间：
2023
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背景：轮班工人所经历的自然光周期的破坏与癌症发病率的增加有关。几种癌症小鼠模型在暴露于不规则的光/暗周期时会发展出更严重的疾病，这支持了昼夜节律紊乱与癌症风险增加之间的联系。隐花色素 2 (CRY2) 是分子生物钟的抑制成分，可促进癌蛋白 c-MYC 的周转，这是一种可能将分子钟与肿瘤发生联系起来的机制。在 B 细胞中表达转基因 c-MYC 并发展为侵袭性淋巴瘤和白血病的 Eμ-MYC 小鼠中，整体 Cry2 缺失会降低存活率并增强肿瘤形成。模拟轮班工人所经历的破坏的照明条件会抑制 C57BL/6J 小鼠外周组织中的 Cry2 转录本。虽然它比 Cry2 的纯合子缺失要温和，但我们假设 Cry2 节律性的降低可能会改变 MYC 蛋白的积累，并导致昼夜节律紊乱导致的癌症风险增加。我们在 MYC 驱动的淋巴瘤中检验了这一假设。 方法：我们将 Eμ-MYC 小鼠安置在遮光盒中，设置为对照（12 小时光照后 12 小时黑暗的连续循环，LD12:12）或慢性时差反应（每两到三天提前 8 小时光照阶段，CJL）照明条件，并评估中断的光照周期对 Eμ-MYC 小鼠的存活和肿瘤形成的影响。 结果：昼夜节律的环境破坏不会改变 Eμ-MYC 小鼠的肿瘤位置、肿瘤生长或存活率。 结论：昼夜节律光照破坏后 Cry2 节律的减弱比 Cry2 缺失更轻微。昼夜节律基因表达改变导致的表型缺失与 Cry2 纯合缺失导致的肿瘤发生增强相反，表明 CRY2 剂量会影响该模型。重要的是，这些发现表明，与昼夜节律紊乱相关的癌症风险增加是由一种或多种机制引起的，这些机制在此没有概述，并且在不同的肿瘤类型中可能有所不同。
Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eμ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.