2025-06-03 京都大学
PBRM1はVimentin発現制御を介して膵癌の病理学的分化度、転移能、化学療法感受性を制御している。
<関連情報>
- https://www.kyoto-u.ac.jp/ja/research-news/2025-06-03
- https://www.kyoto-u.ac.jp/sites/default/files/2025-05/web_2505_Fukuda-cacf3e2e262f6a6cfdbfb7114c44890a.pdf
- https://www.jci.org/articles/view/177533
ポリブロモ1/ビメンチン軸は膵臓癌の腫瘍悪性度、上皮間葉転換、転移を規定する Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer
Munenori Kawai, Akihisa Fukuda, Munehiro Ikeda, Kei Iimori, Kenta Mizukoshi, Kosuke Iwane, Go Yamakawa, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Tomonori Masuda, Yuichi Fukunaga, Munemasa Nagao, Osamu Araki, Takaaki Yoshikawa, Satoshi Ogawa, Yukiko Hiramatsu, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Dieter Saur,Tatsuaki Tsuruyama, Toshihiko Masui, Etsuro Hatano, and Hiroshi Seno
Journal of Clinical Investigation Published: June 2, 2025
DOI:https://doi.org/10.1172/JCI177533
Abstract
Mutations in Polybromo 1 (PBRM1), a subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, are frequently observed in several cancers, including pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrated that pancreas-specific loss of Pbrm1 in mice harboring Kras mutations and Trp53 deletions accelerated the development of poorly differentiated PDAC, epithelial-mesenchymal transition (EMT), and metastasis, resulting in worsened prognosis. Pbrm1 loss in preexisting PDAC shifted the tumor grade from a well- to a poorly differentiated state and elevated vimentin expression. Pbrm1-null PDAC exhibited downregulation of apical junction genes and upregulation of EMT pathway genes, including the vimentin and squamous molecular subtype signature genes. Mechanistically, PBRM1 bound to the vimentin gene promoter and directly downregulated its expression. Furthermore, suppression of vimentin in Pbrm1-null PDAC cells reversed the dedifferentiation phenotype and reduced EMT and metastasis. Consistently, reduced PBRM1 expression correlated with high vimentin expression, poorly differentiated histology, a high recurrence rate, and reduced overall survival in human PDACs. Additionally, PDAC with PBRM1 deletion was associated with the aggressive squamous molecular subtype. Our data established PBRM1 as a tumor suppressor that controls tumor grade and metastasis of PDAC by regulating vimentin expression.
