• Open Access

Paradoxically enhanced immunoreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in cancer cells at the invasion front

Authors

  • Koki Nagaike,

    1. Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
    2. First Department of Surgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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  • Kazuyo Kohama,

    1. Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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  • Shuichiro Uchiyama,

    1. Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
    2. First Department of Surgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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  • Hiroyuki Tanaka,

    1. Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
    2. Second Department of Surgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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  • Kazuo Chijiiwa,

    1. First Department of Surgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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  • Hiroshi Itoh,

    1. Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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  • Hiroaki Kataokal

    Corresponding author
    1. Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692
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To whom correspondence should be addressed. E-mail: mejina@med.miyazaki-u.ac.jp

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

Ancillary