Yamamoto Akinaru, Kawashima Atsunari, Uemura Toshihiro, Nakano Kosuke, Matsushita Makoto, Ishizuya Yu, Jingushi Kentaro, Hase Hiroaki, Katayama Kotoe, Yamaguchi Rui, Sassi Nesrine, Motoyama Yuichi, Nojima Satoshi, Mita Masashi, Kimura Tomonori, Motooka Daisuke, Horibe Yuki, Okuda Yohei, Oka Toshiki, Yamamichi Gaku, Tomiyama Eisuke, Koh Yoko, Yamamoto Yoshiyuki, Kato Taigo, Hatano Koji, Uemura Motohide, Imoto Seiya, Wada Hisashi, Morii Eiichi, Tsujikawa Kazutake, Nonomura Norio
Department of Urology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Int J Cancer. 2025 Apr 1;156(7):1439-1456. doi: 10.1002/ijc.35295. Epub 2024 Dec 18.
Animal models of N-butyl-N-(4-hydroxy butyl) nitrosamine (BBN)-induced urothelial carcinoma (UC), particularly bladder cancer (BC), have long been established. However, the rare incidence of BBN-induced upper urinary tract UC (UTUC), which originates from the same urothelium as BC, remains elusive. The scarcity of animal models of UTUC has made it challenging to study the biology of UTUC. To address this problem, we tried to establish a novel mouse model of UTUC by treating multiple mice strains and sexes with BBN. The molecular consistency between the UTUC mouse model and human UTUC was confirmed using multi-omics analyses, including whole-exome, whole-transcriptome, and spatial transcriptome sequencing. 16S ribosomal RNA metagenome sequencing, metabolome analysis, and dietary interventions were employed to assess changes in the gut microbiome, metabolome, and carcinogenesis of UTUC. Of all treated mice, only female BALB/c mice developed UTUC over BC. Multi-omics analyses confirmed that the UTUC model reflected the molecular characteristics and heterogeneity of human UTUC with poor prognosis. Furthermore, the model exhibited increased Tnf-related inflammatory gene expression in the upper urinary tract and a low relative abundance of Parabacteroides distasonis in the gut. Dietary intervention, mainly without alanine, led to P. distasonis upregulation and successfully prevented UTUC, as well as suppressed Tnf-related inflammatory gene expression in the upper urinary tract despite the exposure to BBN. This is the first report to demonstrate a higher incidence of UTUC than BC in a non-engineered mouse model using BBN. Overall, this model could serve as a useful tool for comprehensively investigating UTUC in future studies.
长期以来，已建立了N-丁基-N-(4-羟基丁基)亚硝胺（BBN）诱导的尿路上皮癌（UC）动物模型，尤其是膀胱癌（BC）模型。然而，BBN诱导的上尿路UC（UTUC）发病率较低，它与BC起源于相同的尿路上皮，其发病机制仍不清楚。UTUC动物模型的稀缺使得研究UTUC生物学具有挑战性。为了解决这个问题，我们试图通过用BBN处理多种小鼠品系和性别来建立一种新型的UTUC小鼠模型。使用多组学分析，包括全外显子组、全转录组和空间转录组测序，证实了UTUC小鼠模型与人类UTUC之间的分子一致性。采用16S核糖体RNA宏基因组测序、代谢组分析和饮食干预来评估UTUC肠道微生物组、代谢组和致癌作用的变化。在所有接受治疗的小鼠中，只有雌性BALB/c小鼠发生了UTUC而非BC。多组学分析证实，UTUC模型反映了预后不良的人类UTUC的分子特征和异质性。此外，该模型在上尿路中Tnf相关炎症基因表达增加，肠道中狄氏副拟杆菌的相对丰度较低。主要不含丙氨酸的饮食干预导致狄氏副拟杆菌上调，并成功预防了UTUC，尽管暴露于BBN，但也抑制了上尿路中Tnf相关炎症基因的表达。这是第一份报告，证实在使用BBN的非工程小鼠模型中，UTUC的发病率高于BC。总体而言，该模型可作为未来研究中全面研究UTUC的有用工具。
