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

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.

• Authors: Yuki Shibayama, Kazuo Takahashi, Hisateru Yamaguchi, Jun Yasuda, Daisuke Yamazaki, Asadur Rahman, Takayuki Fujimori, Yoshihide Fujisawa, Shinji Takai, Toru Furukawa, Tsutomu Nakagawa, Hiroyuki Ohsaki, Hideki Kobara, Jing Hao Wong, Tsutomu Masaki, Yukio Yuzawa, Hideyasu Kiyomoto, Shinichi Yachida, Akihiro Fujimoto, Akira Nishiyama
• Journal: Communications biology (Commun Biol) Vol. 3 Issue 1 Pg. 724 (11 27 2020) ISSN: 2399-3642 [Electronic] England
• PMID: 33247206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP6AP2 protein, human
• Chromosomal Proteins, Non-Histone
• Receptors, Cell Surface
• Adenosine Triphosphatases
• SMARCA5 protein, human
• Vacuolar Proton-Translocating ATPases

Topics

• Adenosine Triphosphatases (genetics, metabolism)
• Animals
• Carcinoma, Pancreatic Ductal (genetics, metabolism)
• Cell Line
• Cell Transformation, Neoplastic
• Chromatin Assembly and Disassembly
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Genomic Instability
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Pancreatic Neoplasms (genetics, metabolism)
• Receptors, Cell Surface (metabolism)
• Up-Regulation
• Vacuolar Proton-Translocating ATPases (metabolism)
• Whole Genome Sequencing