异常的（前）肾素受体表达通过上调SMARCA5/SNF2H诱导胰腺导管腺癌中的基因组不稳定。

Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H.

作者信息

Shibayama Yuki, Takahashi Kazuo, Yamaguchi Hisateru, Yasuda Jun, Yamazaki Daisuke, Rahman Asadur, Fujimori Takayuki, Fujisawa Yoshihide, Takai Shinji, Furukawa Toru, Nakagawa Tsutomu, Ohsaki Hiroyuki, Kobara Hideki, Wong Jing Hao, Masaki Tsutomu, Yuzawa Yukio, Kiyomoto Hideyasu, Yachida Shinichi, Fujimoto Akihiro, Nishiyama Akira

机构信息

Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan.

Department of Nephrology, Fujita Health University School of Medicine, Aichi, 470-1192, Japan.

出版信息

Commun Biol. 2020 Nov 27;3(1):724. doi: 10.1038/s42003-020-01434-x.

DOI:10.1038/s42003-020-01434-x

PMID:33247206

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7695732/

Abstract

(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.

摘要

（前）肾素受体[（P）RR]在多种疾病中发挥作用，如心血管和肾脏疾病以及癌症。异常的（P）RR表达在最常见的胰腺癌——胰腺导管腺癌（PDAC）中普遍存在。在此，我们展示了（P）RR的异常表达是否直接导致人胰腺导管上皮（HPDE）细胞的基因组不稳定。表达（P）RR的HPDE细胞表现出明显的细胞异型性。全基因组测序显示，异常的（P）RR表达在基因组水平上诱导大量点突变和结构变异。一个表达（P）RR的细胞群体表现出肿瘤形成能力，显示出以独特核体为特征的非典型细胞核和染色体异常。（P）RR的过表达通过直接分子相互作用上调与SWItch/蔗糖非发酵（SWI/SNF）相关、基质相关、肌动蛋白依赖性染色质调节因子、亚家族a、成员5（SMARCA5），这导致几种基因组稳定性途径失效。这些数据表明，异常的（P）RR表达促成了PDAC的早期致癌过程。