Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: Role of uric acid accumulation in gemcitabine-induced MICA/B expression

BMC Cancer

Xiulong Xu²  Geetha S Rao²  Veronika Groh³  Thomas Spies³  Paolo Gattuso¹  Howard L Kaufman⁵  Janet Plate⁵  Richard A Prinz⁴ 

[1] Department of Pathology, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA

[2] Department of General Surgery, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA

[3] Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA

[4] Department of Surgery, NorthShore University Health System, Evanston, IL 60201, USA

[5] Department of Immunology/Microbiology, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA

关键词: DNA damage;    Allopurinol;    Uric acid;    Gemcitabine;    MICA/B;    Pancreatic cancer;   

Others  :  1080941
DOI  :  10.1186/1471-2407-11-194

 received in 2010-10-15, accepted in 2011-05-23,  发布年份 2011

【 摘 要 】

Background

Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity.

Methods

Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a ⁵¹Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively.

Results

Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil.

Conclusions

The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production.

【 授权许可】

   
2011 Xu et al; licensee BioMed Central Ltd.

【 图 表 】

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