Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia

Authors

  • Elizabeth C. Wick MD,

    Corresponding author
    1. *Department of Surgery, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
    • 600 N Wolfe St., Blalock 658, Baltimore, MD 21287
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  • Robert E. LeBlanc MD,

    1. Department of Pathology, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Guillermo Ortega BA,

    1. Department of Medicine, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Chelsea Robinson,

    1. *Department of Surgery, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Elizabeth Platz PhD,

    1. Department of Epidemiology, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Drew M. Pardoll MD, PhD,

    1. Department of Oncology, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Chris Iacobuzio-Donahue MD, PhD,

    1. Department of Pathology, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Cynthia L. Sears MD

    1. Department of Medicine, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, Maryland
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  • Supported by National Institutes of Health (NIH) grants R01 CA151393 (to C.L.S.), RO1 CA 091409 (to C.L.S.), RO1 DK 45496 (to C.L.S.), RO1 DK 080817 (to C.L.S.), K08 DK 087856 (to E.C.W.), and American Society of Colorectal Surgeons Career Development Award (to E.C.W.).

Abstract

Background:

Activated Stat3 is an important mediator of oncogenesis in the colon. To test the hypothesis that select Stat activation and/or the pattern of Stat activation serves as a marker for early neoplastic transformation, we examined the distribution of activated Stat1(pStat1), Stat6(pStat6), and Stat3(pStat3) in colitis along the continuum of inactive disease to colitis-associated cancer.

Methods:

Tissue microarrays were constructed using colonoscopy biopsy and surgical specimens from 67 patients with ulcerative colitis or Crohn's colitis and 11 controls. In all, 111 sets of samples were analyzed representing normal tissue, active disease, low-grade dysplasia, high-grade dysplasia, and colitis-associated cancer. Immunohistochemistry to detect pStat1, pStat6, and pStat3 in colonic epithelial and mucosal immune cells was then correlated with clinical and pathological data (tumor location, histologic type, grade, and lymph node involvement).

Results:

In 50% of colitis-associated cancer samples, pStat3 was detected prominently in epithelial cells, where it was routinely associated with intense pStat3 staining in surrounding immune cells. Stat3 activation was greater in low-grade tumors than in high-grade ones (P < 0.05). pStat6 expression was more common in normal tissues than in colitis-associated cancer (P < 0.05). pStat1 was detected in a small subset of immune cells in patients with chronic inactive and active colitis, low- and high-grade dysplasia, but not in colitis-associated cancer.

Conclusions:

pStat3 may be a marker for neoplastic transformation in patients with colitis. A shift from predominant immune cell Stat6 activation to Stat3 activation accompanies the onset of dysplasia with concomitant increased epithelial cell Stat3 activation in a subset of patients. (Inflamm Bowel Dis 2011;)

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