从核架构看用于研究人类辐射诱导甲状腺癌的动物模型的适宜性：证据。

Suitability of animal models for studying radiation-induced thyroid cancer in humans: evidence from nuclear architecture.

机构信息

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

出版信息

Thyroid. 2011 Dec;21(12):1331-7. doi: 10.1089/thy.2011.0269.

DOI:10.1089/thy.2011.0269

PMID:22136268

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3229820/

Abstract

BACKGROUND

Rat and mouse have been widely used to estimate the radiation risk and tumorigenic effects of radiation with extrapolating the findings to humans. RET/PTC is a characteristic genetic alteration frequently found in radiation-induced thyroid cancer in human populations. Recently, nuclear architecture and spatial proximity between recombinogenic genes have been implicated as important factors in the generation of RET/PTC and other chromosomal rearrangements in human cells. However, it is unknown whether the nuclear architecture in rodent thyroid cells is similar to that of human thyroid cells. The aim of this study was to test whether the proximity effects that are observed between loci involved in RET/PTC rearrangements in humans are conserved across different species.

METHODS

Using 3D fixation, fluorescence in situ hybridization, and confocal microscopy, we compared the distance between genes involved in RET/PTC rearrangement in normal thyroid cells from humans, mice, and rats.

RESULTS

While in humans, RET, NCOA4, and H4 are all located on the same chromosome (10q), in rodents these genes are located on separate chromosomes. In mouse, RET is located on chromosome 6F1, NCOA4 on 14B, and H4 on 10B5.3. In rat, RET is on chromosome 4q42, NCOA4 on 16p16, and H4 (TST1) on 9q36. We further observed that in human thyroid cells, mean distance between genes involved in two most common types of RET/PTC, that is, RET and NCOA4 (partners of RET/PTC3) and RET and H4 (partners of RET/PTC1), was 1.08±0.04 and 1.24±0.05 μm, respectively. In mouse thyroid cells, these distances were 3.21±0.1 and 3.43±0.1 μm, and in rat cells the values were 3.37±0.1 and 3.87±0.1 μm (p<0.001). Moreover, we found that in contrast to human thyroid cells, in rodent cells these genes were randomly positioned with respect to each other.

CONCLUSIONS

The differences in nuclear architecture and spatial positioning of genes involved in RET/PTC rearrangements between human and rodent thyroid cells raise a concern about suitability of animal models for assessing RET/PTC-driven thyroid carcinogenesis in humans.

摘要

背景

大鼠和小鼠被广泛用于估计辐射风险和肿瘤形成效应，将研究结果外推至人类。RET/PTC 是人类人群中放射性诱导甲状腺癌中经常发现的一种特征性遗传改变。最近，核结构和重组基因之间的空间接近被认为是人类细胞中产生 RET/PTC 和其他染色体重排的重要因素。然而，尚不清楚啮齿动物甲状腺细胞中的核结构是否与人类甲状腺细胞相似。本研究旨在测试在人类中观察到的涉及 RET/PTC 重排的基因之间的接近效应是否在不同物种中保守。

方法

使用 3D 固定、荧光原位杂交和共聚焦显微镜，我们比较了来自人类、小鼠和大鼠正常甲状腺细胞中涉及 RET/PTC 重排的基因之间的距离。

结果

虽然在人类中，RET、NCOA4 和 H4 均位于同一染色体（10q）上，但在啮齿动物中这些基因位于不同的染色体上。在小鼠中，RET 位于 6F1 染色体上，NCOA4 位于 14B 染色体上，H4 位于 10B5.3 染色体上。在大鼠中，RET 位于 4q42 染色体上，NCOA4 位于 16p16 染色体上，H4（TST1）位于 9q36 染色体上。我们进一步观察到，在人类甲状腺细胞中，涉及两种最常见的 RET/PTC 类型的基因之间的平均距离，即 RET 和 NCOA4（RET/PTC3 的伴侣）和 RET 和 H4（RET/PTC1 的伴侣），分别为 1.08±0.04μm 和 1.24±0.05μm。在小鼠甲状腺细胞中，这些距离分别为 3.21±0.1μm 和 3.43±0.1μm，而在大鼠细胞中，这些值分别为 3.37±0.1μm 和 3.87±0.1μm（p<0.001）。此外，我们发现与人类甲状腺细胞相反，在啮齿动物细胞中，这些基因彼此之间随机定位。