Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer.

Abstract

Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitis-associated cancer.

• 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: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 42 Pg. 17420-5 (Oct 18 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21969570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Peptide Fragments
• RNA, Messenger
• RNA, Neoplasm
• Receptors, Neurokinin-1
• Substance P

Topics

• Alternative Splicing
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Colitis, Ulcerative (complications, genetics, metabolism, pathology)
• Colon (metabolism, pathology)
• Colorectal Neoplasms (etiology, genetics, metabolism, pathology)
• Humans
• Intestinal Mucosa (metabolism, pathology)
• Ligands
• Models, Molecular
• Peptide Fragments (chemistry, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Receptors, Neurokinin-1 (chemistry, genetics, metabolism)
• Substance P (metabolism)