Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis

J. Selzer-Plon, J. Bornholdt, S. Friis, H. C. Bisgaard, I. M. B. Lothe, K. M. Tveit, E. H. Kure, Ulla Birgitte Vogel, L. K. Vogel

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Abstract

Background: Clinical trials where cancer patients were treated with protease inhibitors have suggested that the serine protease, prostasin, may act as a tumour suppressor. Prostasin is proteolytically activated by the serine protease, matriptase, which has a very high oncogenic potential. Prostasin is inhibited by protease nexin-1 (PN-1) and the two isoforms encoded by the mRNA splice variants of hepatocyte growth factor activator inhibitor-1 (HAI-1), HAI-1A, and HAI-1B. Methods: Using quantitative RT-PCR, we have determined the mRNA levels for prostasin and PN-1 in colorectal cancer tissue (n = 116), severe dysplasia (n = 13), mild/moderate dysplasia (n = 93), and in normal tissue from the same individuals. In addition, corresponding tissues were examined from healthy volunteers (n = 23). A part of the cohort was further analysed for the mRNA levels of the two variants of HAI-1, here denoted HAI-1A and HAI-1B. mRNA levels were normalised to beta-actin. Immunohistochemical analysis of prostasin and HAI-1 was performed on normal and cancer tissue. Results: The mRNA level of prostasin was slightly but significantly decreased in both mild/moderate dysplasia (p <0.001) and severe dysplasia (p <0.01) and in carcinomas (p <0.05) compared to normal tissue from the same individual. The mRNA level of PN-1 was more that two-fold elevated in colorectal cancer tissue as compared to healthy individuals (p <0.001) and elevated in both mild/moderate dysplasia (p <0.01), severe dysplasia (p <0.05) and in colorectal cancer tissue (p <0.001) as compared to normal tissue from the same individual. The mRNA levels of HAI-1A and HAI-1B mRNAs showed the same patterns of expression. Immunohistochemistry showed that prostasin is located mainly on the apical plasma membrane in normal colorectal tissue. A large variation was found in the degree of polarization of prostasin in colorectal cancer tissue. Conclusion: These results show that the mRNA level of PN-1 is significantly elevated in colorectal cancer tissue. Future studies are required to clarify whether down-regulation of prostasin activity via up regulation of PN-1 is causing the malignant progression or if it is a consequence of it.
Original languageEnglish
JournalB M C Cancer
Volume9
Pages (from-to)201
ISSN1471-2407
DOIs
Publication statusPublished - 2009

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Selzer-Plon, J., Bornholdt, J., Friis, S., Bisgaard, H. C., Lothe, I. M. B., Tveit, K. M., Kure, E. H., Vogel, U. B., & Vogel, L. K. (2009). Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis. B M C Cancer, 9, 201. https://doi.org/10.1186/1471-2407-9-201