Interferon alpha induction of Stat1 and Stat2 and their prognostic significance in carcinoid tumors.
IFN-alpha has been shown to elicit antitumor activity in carcinoid tumors. In the present study the effects of IFN-alpha on the protein expression involved in the IFN-alpha signaling, which were recognized as signal transducer and activators of transcription (Stats), were investigated. Archive specimens from 45 carcinoid patients, 33 before IFN-alpha and 45 during treatment, were studied. The tissues were immunostained for protein expression by using monoclonal anti-Stat1 and anti-Stat2 antibodies. Results showed that Stat1 and Stat2 immunostaining were significantly increased during IFN-alpha treatment. Stats scores were significantly increased only in patients with objective response as well as those with stable disease but not in those with progressive disease. The induction of Stats correlated with the survival rates of the patients. In addition, both Stat scores significantly correlated with the p68 protein expression. In a carcinoid tumor cell line, Bon1, IFN-alpha dose-dependently increased the Stat expression. Analysis of cell fractions showed that IFN-alpha increased Stat protein both in cytoplasm and nucleoplasm of the cells. Furthermore, IFN-alpha enhanced tyrosine phosphorylation of Stat1 and Stat2. Thus, the antitumor effect, in vivo and in vitro, in IFN-alpha-treated carcinoid tumors seems to be mediated via upregulation of Stat proteins and enhancement of phosphorylation of these proteins.
Zhou
Y
Y
Endocrine Oncology Unit of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
Wang
S
S
Gobl
A
A
Oberg
K
K
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D007124:Immunoenzyme Techniques; D016898:Interferon-alpha / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011233:Precipitin Tests; D011379:Prognosis; D011494:Protein Kinases / Q000378:metabolism; D012189:Retrospective Studies; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015996:Survival Rate; D015534:Trans-Activators / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D011494:Protein Kinases