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Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant 81201727), the National High Technology Research and Development Program of China (2012aA02A503), the open project of State Key Laboratory of Molecular Oncology (SKL-KF-2013-14), the Major Platform Project Funds of Administration of Ocean and Fisheries of Guangdong, China (GD2012-D01-002), the Science and Technology Program of Guangzhou, China (2011Y1-00022), the China Postdoctoral Science Foundation (Grants 2012M511882, 2013T60827), the Science and Technology Innovation Key Project of Guangdong Higher Education Institutes (CXZD1110), Science and Technology Program of Guangzhou (2014J4100103), and the Natural Science Foundation of Guangdong Province (Grant S2012040006873).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Medical College, Guangdong Province Key Laboratory of Molecule Immunology and Antibody Engineering, Jinan University, Guangzhou, 510632, People’s Republic of China

    Haiying Li, Yong Zhang, Jiwei Ma & Xueyun Zhong

  2. Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, 510632, Guangdong Province, People’s Republic of China

    Xiao Wang, Yuting Liu & Yifei Wang

  3. Institute of Molecular Medicine, Department of Medicine, Shenzhen University, Shenzhen, People’s Republic of China

    Shaoxiang Wang

  4. The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, People’s Republic of China

    Zhan Du & Jie Luo

  5. Department of Radiation Oncology, Cancer Centre, Sun Yat-sen University, Guangzhou, 510120, Guangdong Province, People’s Republic of China

    Weiwei Xiao

Authors
  1. Shaoxiang Wang
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  2. Zhan Du
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  3. Jie Luo
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  4. Xiao Wang
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  5. Haiying Li
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  6. Yuting Liu
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  7. Yong Zhang
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  8. Jiwei Ma
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  9. Weiwei Xiao
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  10. Yifei Wang
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  11. Xueyun Zhong
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Corresponding authors

Correspondence to Yifei Wang or Xueyun Zhong.

Additional information

Shaoxiang Wang and Zhan Du have contributed equally to this study.

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Wang, S., Du, Z., Luo, J. et al. Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer. J Cancer Res Clin Oncol 141, 1405–1416 (2015). https://doi.org/10.1007/s00432-014-1896-8

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  • DOI: https://doi.org/10.1007/s00432-014-1896-8

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