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The basic helix-loop-helix transcription factor E47 reprograms human pancreatic cancer cells to a quiescent acinar state with reduced tumorigenic potential

Authors
 SangWun Kim  ;  Reyhaneh Lahmy  ;  Chelsea Riha  ;  Challeng Yang  ;  Brad L. Jakubison  ;  Jaco van Niekerk  ;  Claudio Staub  ;  Yifan Wu  ;  Keith Gates  ;  Duc Si Dong  ;  Stephen F. Konieczny  ;  Pamela Itkin-Ansari 
Citation
 Pancreas, Vol.44(5) : 718-727, 2015 
Journal Title
 Pancreas 
ISSN
 0885-3177 
Issue Date
2015
MeSH
Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism* ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism* ; Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Pancreatic Ductal/prevention & control ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Cell Proliferation ; Cellular Reprogramming* ; Cellular Senescence* ; Gene Expression Regulation, Neoplastic ; Genetic Therapy ; Humans ; Mice, SCID ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism* ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/prevention & control ; Phenotype ; RNA Interference ; Time Factors ; Transfection ; Up-Regulation ; Xenograft Model Antitumor Assays
Keywords
pancreatic ductal adenocarcinoma ; ID3 ; bHLH signaling ; E47 ; reprogramming
Abstract
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) initiates from quiescent acinar cells that attain a Kras mutation, lose signaling from basic helix-loop-helix (bHLH) transcription factors, undergo acinar-ductal metaplasia, and rapidly acquire increased growth potential. We queried whether PDA cells can be reprogrammed to revert to their original quiescent acinar cell state by shifting key transcription programs. METHODS: Human PDA cell lines were engineered to express an inducible form of the bHLH protein E47. Gene expression, growth, and functional studies were investigated using microarray, quantitative polymerase chain reaction, immunoblots, immunohistochemistry, small interfering RNA, chromatin immunoprecipitation analyses, and cell transplantation into mice. RESULTS: In human PDA cells, E47 activity triggers stable G0/G1 arrest, which requires the cyclin-dependent kinase inhibitor p21 and the stress response protein TP53INP1. Concurrently, E47 induces high level expression of acinar digestive enzymes and feed forward activation of the acinar maturation network regulated by the bHLH factor MIST1. Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis. CONCLUSIONS: Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential. Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate.
Files in This Item:
T201502681.pdf Download
DOI
10.1097/MPA.0000000000000328
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sang Wun(김상운) ORCID logo https://orcid.org/0000-0002-8342-8701
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140670
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