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

Cancer Sci. 2004 Sep;95(9):728-35. doi: 10.1111/j.1349-7006.2004.tb03253.x.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cadherins / metabolism
  • Cell Membrane / metabolism
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Epitopes / immunology
  • Female
  • Humans
  • Immunoglobulin G / immunology
  • In Situ Hybridization
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Middle Aged
  • Neoplasm Invasiveness / pathology*
  • Peptide Fragments / immunology
  • Proteinase Inhibitory Proteins, Secretory
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rabbits


  • Cadherins
  • Epitopes
  • Immunoglobulin G
  • Membrane Glycoproteins
  • Peptide Fragments
  • Proteinase Inhibitory Proteins, Secretory
  • RNA, Messenger
  • SPINT1 protein, human