Abstract
We have previously demonstrated significantly decreased immu‐noreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI‐1), an integral membrane protein that exhibits potent inhibitory activity against hepatocyte growth factor activator (HGFA) and matriptase, in colorectal adenocarcinomas. In this report, we describe further detailed analysis of HAI‐1 expression in colorectal adenocarcinoma by using three kinds of anti‐HAI‐1 antibodies, each of which recognizes a distinct epitope of the HAI‐1 molecule, and also by in‐situ hybridization for HAI‐1 mRNA. The results indicated that the decreased immunoreactivity of HAI‐1 in colorectal carcinoma cells is largely a result of enhanced ecto‐domain shedding of HAI‐1 in these cells. In contrast, immunore‐activity of mature membrane‐form HAI‐1 was paradoxically enhanced in cancer cells at the invasion front, showing intense cell‐stroma interactions and/or sprouting invasion. This finding indicates that these invading cells showed decreased ectodomain shedding of HAI‐1 and consequently might require the existence of the membrane‐form HAI‐1. Of particular interest was the observation of a possible inverse correlation between paradoxical up‐regulation of membrane‐form HAI‐1 expression and membrane‐associated E‐cadherin in these cells. These membrane‐form HAI‐1‐positive sprouting cancer cells were also negative for MIB‐1 immunohistochemically, indicating a low‐proliferating population. All these results suggest that HAI‐1 may mediate diverse functions in regard to the progression of colorectal carcinomas, and the immunoreactivity of membrane‐form HAI‐1 may serve as a marker of invading cancer cells.
Abbreviations:
- HAI‐1
hepatocyte growth factor activator inhibitor type 1
- HGF
hepatocyte growth factor
- HGFA
hepatocyte growth factor activator
- SF
scatter factor
- sHAI‐1
secreted‐form HAI‐1
- KD1
first Kunitz domain
- KD2
second Kunitz domain
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