Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells.
OBJECTIVE
Ninjurin1 is a novel adhesion molecule that has a role in promoting nerve regeneration. Although ninjurin1 is ubiquitously expressed in various human tissues, including the liver, the biologic functions of ninjurin1 in tissues other than the nervous system remain unknown. The aim of this study was to investigate the function of ninjurin1 in hepatocytes.


METHODS
The effect of ninjurin1 overexpression was examined in Huh-7 hepatoma cells. Ninjurin1 expression was examined by Western blot in human hepatocellular carcinoma tissues as well as their adjacent liver tissues.


RESULTS
Ninjurin1-overexpressing clones exhibited strong growth inhibition due to G1 cell cycle arrest, which is associated with a posttranscriptional increase in p21WAF1/Cip1, a decrease of cyclin-dependent kinase 2 activity and the hypophosphorylation of Rb. The ninjurin1-overexpressing clones had increased senescence-associated beta-galactosidase activity and autofluorescent pigment, characteristic features of cellular senescence. The levels of ninjurin1 expression were higher in hepatocellular carcinoma tissues than those in adjacent liver tissues.


CONCLUSIONS
The present study provides the first evidence that ninjurin1 is able to induce the senescence program. Ninjurin1 may be involved in the regulation of cellular senescence in the liver during carcinogenesis.
Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. toyamat@moltx.med.osaka-u.ac.jp
Takashi
T
Toyama
Yutaka
Y
Sasaki
Masayoshi
M
Horimoto
Kenya
K
Iyoda
Takayuki
T
Yakushijin
Kazuyoshi
K
Ohkawa
Tetsuo
T
Takehara
Akinori
A
Kasahara
Toshiyuki
T
Araki
Masatsugu
M
Hori
Norio
N
Hayashi
D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015870:Gene Expression / Q000187:drug effects; D005809:Genes, Regulator; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*
C493956:CDKN1A protein, human; D015816:Cell Adhesion Molecules, Neuronal; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C484438:NINJ1 protein, human; D009414:Nerve Growth Factors