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

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

doi:10.1038/s42003-020-01434-x

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.

Highlights

(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer
The activation of Wnt signalling pathway through this molecular interaction is related to the development of PDAC7,13, Glioma14. and colorectal cancer15. (P)RR plays a role in an accessary protein of vacuolar H+-ATPase (V-ATPase)[16], which mediates the acidification of the extracellular space or vesicles to facilitate membrane trafficking and fusion, receptor-mediated endocytosis and autophagic protein degradation17. (P)RR is involved in partitioning defective homologue 3 (Par3) system responsible for apical-basal orientation[18] and noncanonical Wnt planar cell polarity (PCP) pathway for proximal-distal orientation[19,20] in the cellular polarity
The present study demonstrates that aberrant (P)RR expression directly induces genomic instability and tumour-forming ability in human pancreatic ductal epithelial (HPDE) cells

Summary

Introduction

(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. (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. (P)RR plays a role of multiple cellular functions, such as reninangiotensin system, Wnt signalling pathway, extracellular and vesicular acidification, cell polarity and maintenance of the pyruvate dehydrogenase (PDH) complex[8]. Binding of the (P)RR to PDH E1β-subunit (PDHB) contributes to the maintenance of aerobic glucose metabolism[21] Whether these cellular functions dominantly affect the genomic instability under aberrant (P)RR expression remains to be solved

Methods

Results

Conclusion