Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis

TY - JOUR

T1 - Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis

AU - Selzer-Plon, Joanna

AU - Bornholdt, Jette

AU - Friis, Stine

AU - Bisgaard, Hanne

AU - Lothe, Inger

AU - Tveit, Kjell

AU - Kure, Elin

AU - Vogel, Ulla

AU - Vogel, Lotte

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1186/1471-2407-9-201

DO - 10.1186/1471-2407-9-201

M3 - Journal article

C2 - 19555470

SN - 1471-2407

VL - 9

SP - 201

JO - BMC Cancer

JF - BMC Cancer

IS - 1

ER -