title: Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer.
abstract: OBJECTIVE
  Heat shock protein 90 (Hsp90), a potential therapeutic target, has been widely recognized in vitro and in vivo in immunodeficient mice. Here, we aimed to evaluate the role of Hsp90 in an immunocompetent mouse model of esophageal squamous cell cancer (ESCC).
  
  
  METHODS
  The carcinogen 4-nitroquinoline 1-oxide (4NQO) was used to induce ESCC in C57BL/6 mice. Cancer progression was analyzed through observation of appearance, hematoxylin-eosin staining, immunohistochemical detection, and terminal dUTP nick-end labeling analysis.
  
  
  RESULTS
  4NQO led to the progressive appearance of preneoplastic and tumoral lesions in the esophagus, with 100 % incidence of ESCC in situ occurring only after 16 weeks of carcinogen exposure. Most of these lesions evolved spontaneously into highly invasive ESCC even after 4NQO withdrawal (weeks 16-22). Interestingly, there was marked upregulation of Hsp90 and its client proteins in tumoral lesions at 22 weeks. Hsp90 inhibition by intraperitoneal injection of SNX-2112 over the following 2 weeks downregulated AKT and cyclin D1 expression, leading to significant reduction in tumor incidence and prevention of ESCC progression. Moreover, SNX-2112 treatment decreased proliferating cell nuclear antigen expression and increased the number of apoptotic cells in ESCC tissues.
  
  
  CONCLUSIONS
  Our in vivo findings support the contribution of Hsp90 to ESCC progression, which was achieved by stimulating apoptosis and inhibition of cell proliferation, and provide a strong rationale for further evaluation of Hsp90 inhibitors for treating ESCC.
authors.affiliation: Institute of Molecular Medicine, Department of Medicine, Shenzhen University, Shenzhen, People's Republic of China.
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Du
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiwei
authors.initials: J
authors.lastname: Ma
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xiao
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zhong
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002273:Carcinogens; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C534922:SNX 2112; D015112:4-Nitroquinoline-1-oxide