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VPS52 induces apoptosis via cathepsin D in gastric cancer

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Abstract

Vacuolar protein sorting (VPS) genes encode a class of proteins involved in vesicular trafficking. Growing evidence suggests that VPS proteins play roles in tumor biology. Vacuolar protein sorting 52 (VPS52) is involved in retrograde transport of endosomes, and its roles in cancers have not been explored. This study investigated the genetic alterations, protein changes, biological role, and molecular mechanism of VPS52 in gastric cancer. Loss of heterozygosity of VPS52 was detected in 52.9% (9/17) of gastric cancer samples. Twenty-five percent (5/20) gastric cancer samples contained somatic stop-gain mutation of VPS52, two of which also had simultaneous loss of heterozygosity. Lack of VPS52 protein expression in gastric cancer tissue was found compared with pericancerous tissue and was significantly correlated with more advanced TNM staging and shorter 3-year overall survival. Overexpression of VPS52 significantly reduced viability and increased apoptosis in gastric cancer cells in vitro and reduced tumor volume and tumor weight in xenograft model in vivo. Activation of the cathepsin D/Bax/cytochrome C/caspase 9/caspase 3 pathway was detected in gastric cancer cells overexpressing VPS52. Collectively, VPS52 is a tumor suppressor gene in gastric cancer and could be used as a biomarker. VPS52 adenovirus could be a novel anti-tumor reagent for future gene therapy.

Key messages

  • Loss of heterozygosity and stop-gain mutation of VPS52 were found in gastric cancer.

  • Negative expression of VPS52 significantly correlated with poor prognosis.

  • VPS52 inhibited viability and induced apoptosis of gastric cancer cells in vitro.

  • VPS52 reduced tumor volume and tumor weight in vivo.

  • VPS52 activated the apoptotic pathway through cathepsin D in gastric cancer cells.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81101499), Shanghai Natural Science Foundation (11ZR1407600, 17ZR1405700), and Shanghai Municipal Commission of Health and Family Planning (201640069).

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Authors and Affiliations

  1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270 Dong’an Rd, Shanghai, 200032, People’s Republic of China

    Jian Zhang, Ying Lin, Xichun Hu, Zheng Wu & Weijian Guo

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China

    Jian Zhang, Ying Lin, Xichun Hu, Zheng Wu & Weijian Guo

Authors
  1. Jian Zhang
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  2. Ying Lin
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  3. Xichun Hu
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  4. Zheng Wu
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  5. Weijian Guo
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Corresponding author

Correspondence to Jian Zhang.

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Ethics approval

This study was approved by the Clinical Research Ethics Committee of Fudan University Shanghai Cancer Center. All samples of patients obtained were acquired from the tissue bank of Fudan University Shanghai Cancer Center. Consents for the use of surgical samples were given from patients before surgery and all procedures were in accordance with the Declaration of Helsinki.

All animal procedures in this study complied with protocols approved by the Shanghai Medical Experimental Animal Care Commission.

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None.

Additional information

Jian Zhang and Ying Lin contribute equally.

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Zhang, J., Lin, Y., Hu, X. et al. VPS52 induces apoptosis via cathepsin D in gastric cancer. J Mol Med 95, 1107–1116 (2017). https://doi.org/10.1007/s00109-017-1572-y

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  • DOI: https://doi.org/10.1007/s00109-017-1572-y

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