BACKGROUND: Patients with long-term ulcerative colitis are at risk for developing colorectal cancer. METHODS: Archival formalin-fixed paraffin-embedded tissue from ulcerative colitis patients who underwent a colectomy for high-grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor-1 (PAI-1) as well as other mediators of inflammation-associated cancer. Epithelia from areas of colons that showed histologic evidence of carcinoma, high-grade dysplasia, and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation (quiescent colitis) was microdissected using laser capture microscopy. mRNA was extracted from the microdissected tissue and PCR array analysis was performed. To extend our findings, PAI-1 protein levels were determined using immunohistochemistry. RESULTS: The mRNA expression of PAI-1 is increased 6-fold (p=0.02) when comparing the carcinoma group to the quiescent colitis group; increases were also observed in NFKB2, REL, SRC, and VEGFA. The protein levels of PAI-1 are increased by 50% (p<0.001) in high-grade dysplasia and by 60% (p<0.001) in carcinoma when compared to the quiescent colitis group. CONCLUSIONS: The increase in PAI-1 in high-grade dysplasia and carcinoma suggests a functional role for PAI-1 in malignant transformation in colitis-associated cancer. PAI-1 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis-associated cancer.
BACKGROUND:Patients with long-term ulcerative colitis are at risk for developing colorectal cancer. METHODS: Archival formalin-fixed paraffin-embedded tissue from ulcerative colitispatients who underwent a colectomy for high-grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor-1 (PAI-1) as well as other mediators of inflammation-associated cancer. Epithelia from areas of colons that showed histologic evidence of carcinoma, high-grade dysplasia, and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation (quiescent colitis) was microdissected using laser capture microscopy. mRNA was extracted from the microdissected tissue and PCR array analysis was performed. To extend our findings, PAI-1 protein levels were determined using immunohistochemistry. RESULTS: The mRNA expression of PAI-1 is increased 6-fold (p=0.02) when comparing the carcinoma group to the quiescent colitis group; increases were also observed in NFKB2, REL, SRC, and VEGFA. The protein levels of PAI-1 are increased by 50% (p<0.001) in high-grade dysplasia and by 60% (p<0.001) in carcinoma when compared to the quiescent colitis group. CONCLUSIONS: The increase in PAI-1 in high-grade dysplasia and carcinoma suggests a functional role for PAI-1 in malignant transformation in colitis-associated cancer. PAI-1 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis-associated cancer.
Authors: Masayuki Fukata; Limin Shang; Rebeca Santaolalla; John Sotolongo; Cristhine Pastorini; Cecilia España; Ryan Ungaro; Noam Harpaz; Harry S Cooper; Greg Elson; Marie Kosco-Vilbois; Julia Zaias; Maria T Perez; Lloyd Mayer; Arunan S Vamadevan; Sergio A Lira; Maria T Abreu Journal: Inflamm Bowel Dis Date: 2010-11-15 Impact factor: 5.325
Authors: T A Brentnall; D A Crispin; P S Rabinovitch; R C Haggitt; C E Rubin; A C Stevens; G C Burmer Journal: Gastroenterology Date: 1994-08 Impact factor: 22.682
Authors: Earl Gillespie; Susan E Leeman; Luisa A Watts; Jennifer A Coukos; Michael J O'Brien; Sandra R Cerda; Francis A Farraye; Arthur F Stucchi; James M Becker Journal: Proc Natl Acad Sci U S A Date: 2011-10-03 Impact factor: 11.205
Authors: Yabing Chen; Ralph C Budd; Robert J Kelm; Burton E Sobel; David J Schneider Journal: Arterioscler Thromb Vasc Biol Date: 2006-05-18 Impact factor: 8.311
Authors: Sergei Grivennikov; Eliad Karin; Janos Terzic; Daniel Mucida; Guann-Yi Yu; Sivakumar Vallabhapurapu; Jürgen Scheller; Stefan Rose-John; Hilde Cheroutre; Lars Eckmann; Michael Karin Journal: Cancer Cell Date: 2009-02-03 Impact factor: 31.743