Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia.
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.
Department of Surgery, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland, USA. ewick1@jhmi.edu
Elizabeth C
EC
Wick
Robert E
RE
LeBlanc
Guillermo
G
Ortega
Chelsea
C
Robinson
Elizabeth
E
Platz
Drew M
DM
Pardoll
Chris
C
Iacobuzio-Donahue
Cynthia L
CL
Sears
D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D002288:Adenocarcinoma, Mucinous / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D003093:Colitis, Ulcerative / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D010766:Phosphorylation; D011379:Prognosis; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D046888:Tissue Array Analysis
D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human