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

  1. Koki Nagaike1,2,
  2. Kazuyo Kohama1,
  3. Shuichiro Uchiyama1,2,
  4. Hiroyuki Tanaka1,3,
  5. Kazuo Chijiiwa2,
  6. Hiroshi Itoh1,
  7. Hiroaki Kataokal1,*

Article first published online: 19 AUG 2005

DOI: 10.1111/j.1349-7006.2004.tb03253.x

Issue

Cancer Science

Cancer Science

Volume 95, Issue 9, pages 728–735, September 2004

Additional Information

How to Cite

Nagaike, K., Kohama, K., Uchiyama, S., Tanaka, H., Chijiiwa, K., Itoh, H. and Kataokal, H. (2004), Paradoxically enhanced immunoreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in cancer cells at the invasion front. Cancer Science, 95: 728–735. doi: 10.1111/j.1349-7006.2004.tb03253.x

Author Information

  1. 1

    Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692

  2. 2

    First Department of Surgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692

  3. 3

    Second Department of Surgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692

* To whom correspondence should be addressed. E-mail: mejina@med.miyazaki-u.ac.jp

Publication History

  1. Issue published online: 19 AUG 2005
  2. Article first published online: 19 AUG 2005
  3. Received May 17, 2004/Revised July 6, 2004/Accepted July 6, 2004

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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.

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