REG Ialpha protein may function as a trophic and/or anti-apoptotic factor in the development of gastric cancer.
OBJECTIVE
Although a significant amount of regenerating gene (REG) Ialpha protein is present not only in normal gastric mucosa but also in gastric cancer tissues, its pathophysiologic role in gastric cancer development remains unclear. We investigated REG Ialpha protein expression in early gastric cancers, and examined whether cytokines are responsible for REG Ialpha gene expression and whether REG Ialpha protein has a trophic and/or an antiapoptotic effect on gastric cancer cells.


METHODS
Early gastric cancer specimens were analyzed histologically using immunohistochemistry for REG Ialpha protein and proliferating cell nuclear antigen (PCNA). The effects of cytokines on REG Ialpha promoter activity and its messenger RNA (mRNA) expression in AGS (a kind of gastric cancer cell line) cells were examined by luciferase reporter assay and Northern blot analysis, respectively. Effects of REG Ialpha protein on cell growth and H2O2-induced apoptosis in AGS cells were examined by 3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling (TUNEL) assays, respectively.


RESULTS
REG Ialpha-positive early gastric cancers showed a significantly higher PCNA labeling index and more severe inflammatory cell infiltration in adjacent gastric mucosa than the negative cancers. REG Ialpha gene expression and its promoter activity were enhanced by interferon (IFN)-gamma and interleukin (IL)-6. REG Ialpha protein promoted cell growth and cell resistance to H2O2-induced apoptosis in AGS cells. These effects were abolished by concomitant treatment with anti-REG Ialpha antibody. REG Ialpha protein enhanced Akt phosphorylation and Bcl-xL expression in AGS cells.


CONCLUSIONS
REG Ialpha gene is inducible by cytokine stimulation and its gene product may function as a mitogenic and/or an antiapoptotic factor in the development of early gastric cancer.
Sekikawa
Akira
A
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Fukui
Hirokazu
H
Fujii
Shigehiko
S
Takeda
Jun
J
Nanakin
Apichart
A
Hisatsune
Hiroshi
H
Seno
Hiroshi
H
Takasawa
Shin
S
Okamoto
Hiroshi
H
Fujimori
Takahiro
T
Chiba
Tsutomu
T
D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005753:Gastric Mucosa / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051847:Lithostathine; D008934:Mitogens / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
D002135:Calcium-Binding Proteins; D015850:Interleukin-6; D051847:Lithostathine; D008934:Mitogens; D009419:Nerve Tissue Proteins; D016877:Oxidants; D018809:Proliferating Cell Nuclear Antigen; C497617:REG1A protein, human; D012333:RNA, Messenger; D007371:Interferon-gamma; D006861:Hydrogen Peroxide