Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis.

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.

• Authors: Joanna Selzer-Plon, Jette Bornholdt, Stine Friis, Hanne C Bisgaard, Inger Mb Lothe, Kjell M Tveit, Elin H Kure, Ulla Vogel, Lotte K Vogel
• Journal: BMC cancer (BMC Cancer) Vol. 9 Pg. 201 (Jun 25 2009) ISSN: 1471-2407 [Electronic] England
• PMID: 19555470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Protease Nexins
• Protein Isoforms
• Proteinase Inhibitory Proteins, Secretory
• RNA, Messenger
• Receptors, Cell Surface
• SERPINE2 protein, human
• SPINT1 protein, human
• Serpin E2
• Serine Endopeptidases
• prostasin

Topics

• Aged
• Alternative Splicing
• Amyloid beta-Protein Precursor (biosynthesis)
• Carcinoma (metabolism)
• Cohort Studies
• Colorectal Neoplasms (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Protease Nexins
• Protein Isoforms
• Proteinase Inhibitory Proteins, Secretory (biosynthesis)
• RNA, Messenger (metabolism)
• Receptors, Cell Surface (biosynthesis)
• Serine Endopeptidases (biosynthesis)
• Serpin E2