Abstract
BackgroundIt has recently been shown that overexpression of the serine protease, matriptase, in transgenic mice causes a dramatically increased frequency of carcinoma formation. Overexpression of HAI-1 and matriptase together changed the frequency of carcinoma formation to normal. This suggests that the ratio of matriptase to HAI-1 influences the malignant progression. The aim of this study has been to determine the ratio of matriptase to HAI-1 mRNA expression in affected and normal tissue from individuals with colorectal cancer adenomas and carcinomas as well as in healthy individuals, in order to determine at which stages a dysregulated ratio of matriptase/HAI-1 mRNA is present during carcinogenesis.MethodsUsing quantitative RT-PCR, we have determined the mRNA levels for matriptase and HAI-1 in colorectal cancer tissue (n = 9), severe dysplasia (n = 15), mild/moderate dysplasia (n = 21) and in normal tissue from the same individuals. In addition, corresponding tissue was examined from healthy volunteers (n = 10). Matriptase and HAI-1 mRNA levels were normalized to β-actin.ResultsMatriptase mRNA level was lower in carcinomas compared to normal tissue from healthy individuals (p < 0.01). In accordance with this, the matriptase mRNA level was also lower in adenomas/carcinomas combined as compared to their adjacent normal tissue (p < 0.01). HAI-1 mRNA levels in both normal and affected tissue from individuals with severe dysplasia or carcinomas and in affected tissue with mild/moderate dysplasia were all significantly lower than mRNA levels observed in corresponding tissue from healthy control individuals. HAI-1 mRNA was lower in carcinomas as compared to normal tissue from healthy individuals (p < 0.001). HAI-1 mRNA levels were significantly lower in tissue displaying mild/moderate (p < 0.001) and severe (p < 0.01) dysplasia compared to normal tissue from the same patients. Both adenomas and carcinomas displayed a significantly different matriptase/HAI-1 mRNA ratio than corresponding normal tissue from healthy control individuals (p < 0.05). In addition statistically significant difference (p < 0.001) could be observed between mild/moderate and severe adenomas and their adjacent normal tissue.ConclusionOur results show that dysregulation of the matriptase/HAI-1 mRNA ratio occurs early during carcinogenesis. Future studies are required to clarify whether the dysregulated matriptase/HAI-1 ratio was causing the malignant progression or is a consequence of the same.
Highlights
It has recently been shown that overexpression of the serine protease, matriptase, in transgenic mice causes a dramatically increased frequency of carcinoma formation
The mRNA levels of matriptase and hepatocyte growth factor activator inhibitor 1 (HAI-1) were measured in colon tissue samples from healthy control individuals (n = 10) and in healthy and affected tissue from individuals with mild/moderate dysplasia (n = 21), with severe dysplasia (n = 15) and with colorectal cancer (n = 9) by real-time RT-PCR
HAI-1 and β-actin mRNA's are present with almost the same abundances (Fig. 1 and Table 2) within one order of magnitude
Summary
It has recently been shown that overexpression of the serine protease, matriptase, in transgenic mice causes a dramatically increased frequency of carcinoma formation. Matriptase known as MT-SP1, epithin, TADG-15 and SNC19, is the prototypic member of a recently identified matriptase subfamily of type II transmembrane serine proteases together with matriptase-2 and matriptase-3 [17]. It has a multi-domain structure, including an aminoterminal cytoplasmic tail, a transmembrane region, a sperm protein, enterokinase, and agrin (SEA) domain, two complement subcomponents C1r/Cs, urchin embryonic growth factor and bone morphogenic protein (CUB) domain, four low density lipoprotein receptor class A repeats, and a carboxyl-terminal serine protease domain [1,2,4,8]. HAI-1 knock-out mice die during the embryonic development [16]
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