title: 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.
  
  
  CONCLUSIONS
  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: Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Denmark. selzer@sund.ku.dk
authors: Joanna
authors: J
authors: Selzer-Plon
authors: Jette
authors: J
authors: Bornholdt
authors: Stine
authors: S
authors: Friis
authors: Hanne C
authors: HC
authors: Bisgaard
authors: Inger Mb
authors: IM
authors: Lothe
authors: Kjell M
authors: KM
authors: Tveit
authors: Elin H
authors: EH
authors: Kure
authors: Ulla
authors: U
authors: Vogel
authors: Lotte K
authors: LK
authors: Vogel
mesh_terms: D000368:Aged; D017398:Alternative Splicing; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D002277:Carcinoma / Q000378:metabolism*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D058255:Protease Nexins; D020033:Protein Isoforms; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000096:biosynthesis*; D058258:Serpin E2; D000099271:Prostasin
chemical_list: D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D020033:Protein Isoforms; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012697:Serine Endopeptidases; D058258:Serpin E2; D000099271:Prostasin; C545486:SERPINE2 protein, human; C109149:SPINT1 protein, human