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B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells

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Abstract

B7-H4 is expressed in a variety of tumor cells and functions as a negative regulator of T cells. However, clarification is needed as to whether B7-H4 mediates tumorigenesis through mechanisms, such as apoptosis, in addition to mediating tumor immune escape. We investigate the mechanisms involved in enhanced oncogenicity and the inhibition of apoptosis by B7-H4 in pancreatic cancer cells. Short interfering RNAs (siRNAs) specific for B7-H4 were evaluated for their ability to knockdown B7-H4 mRNA and protein expression in pancreatic cancer cells and the most effective siRNA was selected for investigating the effect of B7-H4 gene silencing in a number of functional assays. The inhibition of B7-H4 increased cell-cell adhesion and decreased the formation of pseudopodia. It also increased the expression of E-cadherin and decreased the expression of vimentin and CD44. B7-H4 siRNA inhibited cell proliferation, colony formation and migration of pancreatic cancer cells. Moreover, increased apoptosis in pancreatic cancer cells following B7-H4 silencing was demonstrated in vitro by using flow cytometry and in a xenograft tumor model and was associated with increased caspase activity and decreased Erk1/2 phosphorylation both in vitro and in vivo. Loss of B7-H4 function thus prevents tumor growth through many processes, including the induction of apoptosis and inhibition of the Erk1/2 signaling pathway indicating that B7-H4 is a cancer promoter and a potentially important therapeutic target. B7-H4 inhibition might offer an exciting opportunity to inhibit the progression of human pancreatic cancers.

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The authors declare no conflicts of interest related to the publication of this work.

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Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, 310003, Hangzhou, China

    Yun Qian, Ling Shen, Zhigang Wu, Hangping Yao & Lihuang Zhang

  2. Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China

    Bo Hong

  3. School of Medicine and Life Sciences, Zhejiang University City College, 51 Huzhou Road, 310015, Hangzhou, China

    Lihuang Zhang

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  1. Yun Qian
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  2. Bo Hong
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  3. Ling Shen
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  4. Zhigang Wu
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  5. Hangping Yao
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  6. Lihuang Zhang
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Corresponding authors

Correspondence to Hangping Yao or Lihuang Zhang.

Additional information

Y.Q. worked on the production of B7-H4 siRNA, animal studies, data acquisition and the analysis and interpretation of data; L.S. and Z.W. carried out the oncobiology studies; B.H. carried out the immunohistochemical staining experiments; H.Y. and L.Z. designed the study and drafted the manuscript. All authors have read and approved the final manuscript.

This work was supported by a grant from the National Natural Science Foundation of China (No. 30972777). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Qian, Y., Hong, B., Shen, L. et al. B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells. Cell Tissue Res 353, 139–151 (2013). https://doi.org/10.1007/s00441-013-1640-8

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  • DOI: https://doi.org/10.1007/s00441-013-1640-8

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