Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer
Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer
复制标题
DOI：
10.1158/1541-7786.mcr-18-0139
复制
发表时间：
2018-08-01
影响因子：
5.2
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Kishikawa, Takahiro;Otsuka, Motoyuki;Koike, Kazuhiko
高度重复的串联阵列，例如染色体着丝粒和着丝粒周围区域的卫星序列，以前被认为是沉默的，但在包括癌症在内的各种生物过程中活跃转录。在胰腺中，这种异常表达甚至出现在 Kras 突变的胰腺上皮内瘤变 (PanIN) 组织（癌前病变）中。为了确定卫星 RNA 在体内致癌过程中的生物学作用，我们构建了表达小鼠主要卫星 (MajSAT) RNA 的转基因小鼠。然而，这些转基因小鼠在正常饲养下并没有表现出自发性恶性肿瘤形成。然而，重要的是，雨蛙素治疗或高脂饮食诱导的胰腺组织中 DNA 损伤增加，这可能是由于 Y-Box 结合蛋白 1 (YBX1)（DNA 损伤修复机制的一个组成部分）的核定位受损所致。此外，当与胰腺特异性 Kras 突变小鼠杂交时，MajSAT RNA 表达导致 PanIN 形成较早增加。这些结果表明，异常的 MajSAT RNA 表达通过增加第二个驱动突变的可能性来加速肿瘤发生，从而加速细胞从突破期退出到扩张期。 (C) 2018 年 AACR。
Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To determine the biological role of satellite RNAs in carcinogenesis in vivo, we constructed mouse major satellite (MajSAT) RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT RNA expression accelerates oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase. (C) 2018 AACR.