Enhanced expression of hepatocyte growth factor activator inhibitor type 2-related small peptide at the invasive front of colon cancers.
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.


OBJECTIVE
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 beta-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.


CONCLUSIONS
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.
Uchiyama
S
S
Department of Pathology, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Itoh
H
H
Naganuma
S
S
Nagaike
K
K
Fukushima
T
T
Tanaka
H
H
Hamasuna
R
R
Chijiiwa
K
K
Kataoka
H
H
D000230:Adenocarcinoma / Q000737:chemistry* / Q000276:immunology / Q000473:pathology; D000236:Adenoma / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D000818:Animals; D016466:CHO Cells; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D004847:Epithelial Cells / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007417:Intestinal Polyps / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D007422:Intestines / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis* / Q000276:immunology; D009687:Nuclear Proteins / Q000032:analysis* / Q000276:immunology; D014157:Transcription Factors / Q000032:analysis* / Q000276:immunology; D051176:beta Catenin / Q000032:analysis
C439765:C19orf33 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051176:beta Catenin