TY - JOUR
T1 - Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H
AU - Shibayama, Yuki
AU - Takahashi, Kazuo
AU - Yamaguchi, Hisateru
AU - Yasuda, Jun
AU - Yamazaki, Daisuke
AU - Rahman, Asadur
AU - Fujimori, Takayuki
AU - Fujisawa, Yoshihide
AU - Takai, Shinji
AU - Furukawa, Toru
AU - Nakagawa, Tsutomu
AU - Ohsaki, Hiroyuki
AU - Kobara, Hideki
AU - Wong, Jing Hao
AU - Masaki, Tsutomu
AU - Yuzawa, Yukio
AU - Kiyomoto, Hideyasu
AU - Yachida, Shinichi
AU - Fujimoto, Akihiro
AU - Nishiyama, Akira
N1 - Funding Information:
We are grateful to Mr Kouichi Yube (Division of Research Instrument and Equipment, Kagawa University) for handling Flow Cytometry and ABI PRISM 3100 Genetic Analyzer, Mr Toru Matsunaga (Department of pathology, Kagawa University Hospital) for performing Papanicolaou stain, Ms Miho Seki (Department of Pharmacology, Faculty of Medicine, Kagawa University) for help with the western blotting and agarose gel electrophoresis, and Mr Yuji Yokota (Department of Pharmacology, Faculty of Medicine, Kagawa University) for taking care of the immunodeficient mice. Mr Koichi Ishiguro (AXIOHELIX Co. Ltd., Okinawa, Japan) also helped to perform the analysis of the human whole-genome sequence. Ms Kanako Ohtsuki created the images of Fig. 7. We also thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This study was supported by Grants-in-Aid for Scientific Research (16K14610 and 19K07690 to Y.S. and 18H03191 to A.N.) from the Ministry of Education, Science and Culture of Japan and from the Tokyo Biomarker Innovation Research Associate (TOBIRA), the Hoansha Foundation and Alumni Association of Kagawa University (Sanjukai).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - (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.
AB - (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.
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U2 - 10.1038/s42003-020-01434-x
DO - 10.1038/s42003-020-01434-x
M3 - Article
C2 - 33247206
AN - SCOPUS:85096697218
VL - 3
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 724
ER -