Paradoxically enhanced immunoreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in cancer cells at the invasion front.
We have previously demonstrated significantly decreased immunoreactivity 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 ectodomain shedding of HAI-1 in these cells. In contrast, immunoreactivity of mature membrane-form HAI-1 was paradoxically en-hanced 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.
Second Department of Pathology, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Koki
K
Nagaike
Kazuyo
K
Kohama
Shuichiro
S
Uchiyama
Hiroyuki
H
Tanaka
Kazuo
K
Chijiiwa
Hiroshi
H
Itoh
Hiroaki
H
Kataoka
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010446:Peptide Fragments / Q000276:immunology; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits
D015820:Cadherins; D000939:Epitopes; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; C109149:SPINT1 protein, human