Proteins that underlie neoplastic progression of ulcerative colitis

Patients with ulcerative colitis (UC) have an increased risk for developing colorectal cancer. Because UC tumorigenesis is associated with genomic field defects that can extend throughout the entire colon, including the non‐dysplastic mucosa, we hypothesized that the same field defects will include abnormally expressed proteins. Here, we applied proteomics to study the protein expression of UC neoplastic progression. The protein profiles of colonic epithelium were compared with (i) UC patients without dysplasia (non‐progressors), (ii) non‐dysplastic colonic tissue from UC patient with high‐grade dysplasia or cancer (progressors), (iii) high‐grade dysplastic tissue from UC progressors, and (iv) normal colon. We identified differential protein expression associated with UC neoplastic progression. Proteins relating to mitochondria, oxidative activity, and calcium‐binding proteins were some of the interesting classes of these proteins. Network analysis discovered that Sp1 and c‐myc proteins may play roles in UC early and late stages of neoplastic progression, respectively. Two over‐expressed proteins in the non‐dysplastic tissue of UC progressors, carbamoyl‐phosphate synthase 1 and S100P, were further confirmed by immunohistochemistry analysis. Our study provides insight into the molecular events associated with UC neoplastic progression, which could be exploited for the development of protein biomarkers in fields of non‐dysplastic mucosa that identify a patient's risk for UC dysplasia.

[1]  M. Kimmey,et al.  DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. , 1992, Gastroenterology.

[2]  J. Jones,et al.  A review of the S100 proteins in cancer. , 2008, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[3]  L. Milani,et al.  An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. , 2007, Human molecular genetics.

[4]  L. Pavelic,et al.  High c-myc protein expression in benign colorectal lesions correlates with the degree of dysplasia. , 1992, Anticancer research.

[5]  N. Ahuja,et al.  Accelerated age-related CpG island methylation in ulcerative colitis. , 2001, Cancer research.

[6]  C. Heizmann,et al.  Immunocytochemical localization of S100A1 in mitochondria on cryosections of the rat heart. , 2007, General physiology and biophysics.

[7]  A. Ahluwalia,et al.  Mesalazine downregulates c‐Myc in human colon cancer cells. A key to its chemopreventive action? , 2007, Alimentary pharmacology & therapeutics.

[8]  W. Chazin,et al.  S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2. , 2008, Biochimica et biophysica acta.

[9]  K. Parker,et al.  Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents*S , 2004, Molecular & Cellular Proteomics.

[10]  Trong Khoa Pham,et al.  Technical, experimental, and biological variations in isobaric tags for relative and absolute quantitation (iTRAQ). , 2007, Journal of proteome research.

[11]  S. Ishiguro,et al.  Increased expression of S100A6 (Calcyclin), a calcium-binding protein of the S100 family, in human colorectal adenocarcinomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  Moritoshi Kinoshita,et al.  Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci , 2002, Hepatology.

[13]  Jasmine L. Gallaher,et al.  Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. , 2008, Gastroenterology.

[14]  Steven P Gygi,et al.  Comparative evaluation of mass spectrometry platforms used in large-scale proteomics investigations , 2005, Nature Methods.

[15]  Henry H. N. Lam,et al.  PeptideAtlas: a resource for target selection for emerging targeted proteomics workflows , 2008, EMBO reports.

[16]  T. Prolla,et al.  The Role of Mitochondrial DNA Mutations in Mammalian Aging , 2007, PLoS genetics.

[17]  N. Lemoine,et al.  Expression of S100P and its novel binding partner S100PBPR in early pancreatic cancer. , 2005, The American journal of pathology.

[18]  M. Bronner,et al.  DNA fingerprinting abnormalities can distinguish ulcerative colitis patients with dysplasia and cancer from those who are dysplasia/cancer-free. , 2003, The American journal of pathology.

[19]  Diane M Simeone,et al.  S100P Promotes Pancreatic Cancer Growth, Survival, and Invasion , 2005, Clinical Cancer Research.

[20]  M. Bronner,et al.  The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. , 2000, The American journal of pathology.

[21]  Shraddha S. Nigavekar,et al.  RAGE Activation by S100P in Colon Cancer Stimulates Growth, Migration, and Cell Signaling Pathways , 2007, Diseases of the colon and rectum.

[22]  Alexey I Nesvizhskii,et al.  Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. , 2002, Analytical chemistry.

[23]  Hongwei Xie,et al.  Identification of carbonylated proteins from enriched rat skeletal muscle mitochondria using affinity chromatography‐stable isotope labeling and tandem mass spectrometry , 2007, Proteomics.

[24]  I. Wierstra,et al.  Sp1: emerging roles--beyond constitutive activation of TATA-less housekeeping genes. , 2008, Biochemical and biophysical research communications.

[25]  M. Bronner,et al.  Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. , 1999, Cancer research.

[26]  J. Yates,et al.  An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database , 1994, Journal of the American Society for Mass Spectrometry.

[27]  D. Ransohoff,et al.  Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. , 1983, Human pathology.

[28]  C. Yeh,et al.  Comparative proteomic studies on the pathogenesis of human ulcerative colitis , 2006, Proteomics.

[29]  G. Rogler,et al.  Differential protein expression profile in the intestinal epithelium from patients with inflammatory bowel disease. , 2007, Journal of proteome research.

[30]  C. Harris,et al.  The reemergence of nitric oxide and cancer. , 2008, Nitric oxide : biology and chemistry.

[31]  F. Waldman,et al.  Chromosomal alterations in ulcerative colitis-related neoplastic progression. , 1997, Gastroenterology.

[32]  L. Robson,et al.  Increased expression of c-myc proto-oncogene in biopsies of ulcerative colitis and Crohn's colitis. , 1992, Gut.

[33]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[34]  N. Oshitani,et al.  Accumulation of mitochondrial DNA mutation with colorectal carcinogenesis in ulcerative colitis , 2005, British Journal of Cancer.

[35]  M. Tuchman,et al.  Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases , 2009, Human mutation.

[36]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[37]  J. Hayashi,et al.  ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis , 2008, Science.

[38]  E. Felley-Bosco,et al.  Proteomics and chronic inflammatory bowel diseases. , 2004, Pathology, research and practice.

[39]  J. Potter,et al.  Chromosomal instability in ulcerative colitis is related to telomere shortening , 2002, Nature Genetics.

[40]  J. Campisi.  Aging, tumor suppression and cancer: high wire-act! , 2004, Mechanisms of Ageing and Development.

[41]  P. Rabinovitch,et al.  Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. , 1994, Gastroenterology.