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Enhanced expression of hepatocyte growth factor activator inhibitor type 2-related small peptide at the invasive front of colon cancers
  1. S Uchiyama1,
  2. H Itoh3,
  3. S Naganuma1,
  4. K Nagaike1,
  5. T Fukushima1,
  6. H Tanaka1,
  7. R Hamasuna4,
  8. K Chijiiwa2,
  9. H Kataoka1
  1. 1Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
  2. 2First Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
  3. 3Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
  4. 4Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
  1. Correspondence to:
    Professor H Kataoka
    Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan;mejina{at}


Background: Hepatocyte growth factor activator inhibitor type 2-related small peptide (H2RSP) is a small nuclear protein abundantly expressed in the gastrointestinal epithelium. However, its functions remain unknown.

Aims: To investigate the expression and localisation of H2RSP in normal, injured and neoplastic human intestinal tissue.

Methods: Immunohistochemical examination and in situ hybridisation for H2RSP were performed using normal and diseased intestinal specimens. Its subcellular localisation and effects on the cellular proliferation and invasiveness were examined using cultured cells.

Results: In the normal intestine, H2RSP was observed in the nuclei of surface epithelial cells and this nuclear localisation was impaired in regenerating epithelium. In vitro, the nuclear translocation of H2RSP was observed along with increasing cellular density, and an overexpression of H2RSP resulted in a reduced growth rate and enhanced invasiveness. H2RSP expression was down regulated in well-differentiated colorectal adenocarcinomas. However, a marked up regulation of the cytoplasmic H2RSP immunoreactivity was observed in cancer cells at the invasive front. These cells showed low MIB-1 labelling, an enhanced p16 expression and nuclear β-catenin. The number of H2RSP-positive cells in the invasive front of well-differentiated adenocarcinomas was considerably higher in the cases with lymph node metastases than in node-negative ones.

Conclusion: In the normal intestine, the nuclear accumulation of H2RSP is a marker of differentiated epithelial cells. Although H2RSP was down regulated in colorectal adenocarcinomas, a paradoxical up regulation was observed in actively invading carcinoma cells. H2RSP immunoreactivity at the invasive front may serve as a marker of invasive phenotype of well-differentiated colon cancers.

  • BSA, bovine serum albumin
  • CHO, Chinese hamster ovary
  • FCS, fetal calf serum
  • HAI-2, hepatocyte growth factor activator inhibitor type 2
  • H2RSP, HAI-2-related small peptide
  • IMUP-1, immortalisation up regulated protein-1
  • ISH, in situ hybridisation
  • LCM, laser-captured microdissection
  • RT-PCR, reverse transcription-polymerase chain reaction
  • PBS, phosphate-buffered saline
  • TBS-T, Tris-buffered saline-Tween 20

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  • Published Online First 29 June 2006

  • Funding: This work was supported by grant-in-aid for scientific research (C) number 17590354 and (B) number 17390116, and 21st Century COE programme (Life Science) from the Ministry of Education, Science, Sports and Culture, Japan, and a grant-in-aid for cancer research from the Ministry of Health, Labor and Welfare and grants from the NOVARTIS Foundation (Japan) for the Promotion of Science and The Naito Foundation.

  • Competing interests: None.