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Open Access Research article

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

Xiulong Xu1*, Geetha S Rao1, Veronika Groh2, Thomas Spies2, Paolo Gattuso3, Howard L Kaufman145, Janet Plate45 and Richard A Prinz16

Author Affiliations

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

2 Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA

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

4 Department of Medicine, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA

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

6 Department of Surgery, NorthShore University Health System, Evanston, IL 60201, USA

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BMC Cancer 2011, 11:194  doi:10.1186/1471-2407-11-194

Published: 23 May 2011

Abstract

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.

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