Interferon-alpha signaling and cell cycle regulation in neuroendocrine tumors of the digestive system
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
The prognosis for untreated carcinoid patients is poor and their quality of life is low. IFN-α treatment has shown a response rate of 50-80%, however, the antitumor mechanism has not been elucidated.
In the present study, 209 specimens representing 92 patients with carcinoid tumors before and during IFN-α treatment were retrospectively selected and histologically confirmed. Tissues were immunostained using different antibodies. IFN-α can significantly upregulate expression of IFN-α receptor (IFN-αR), transcriptional regulatory factors Stats (Stat1, Stat2) and IRFs (IRF-1, IRF-2), as well as p68 (a key enzyme in protein synthesis). IFN-α induction of Stats, IRFs, p68correlates with the clinical response and can be used for evaluating the effectiveness of IFN-αtreatment. Additionally, p68 and Stats may be important prognostic factors in carcinoid patients.
In the in vitro studies, carcinoid tumor cell lines, Bon1 and LCC18, expressing IFNαR and theIFN-inducible genes were used as models of IFN-α action. IFN-α exerts significant antiproliferative effects, upregulates protein expression of IRFs and Stats as well as enhances and/or prolongstyrosine phosphorylation of Stat1, Stat2 and Jak1, Tyk2 kinase. Furthermore, IFN-α changes cell cycle distribution resulting in an accumulation of S-phase populatio This may be due to induced expression of cyclin-dependent kinase inhibitors (CKIs), p21 and p27 aninhibition of the kinase activities of CDK2, CDK3, CDK4, cyclin D1 and cyclin E, b enhancement of cyclin A activity. In addition, IFN-α upregulates Stat1 and Stat2 both in thcytoplasm and in the nucleoplasm as well as promotes translocation of endogenous p21 protein to the nuclei where p21 forms immuno-complexes with Stat1 and Stat2.
In conclusion, these results implicate that the antitumor mechanisms of IFN-α in carcinoidtumors involve regulation of both DNA and protein synthesis, cell cycle progression, signaltransduction, protein trafficking and phosphorylation as well as gene expression.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2000. , 56 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 940
Medical sciences, interferon-α, carcinoid tumors, interferon regulatory factor, p68, PKR, p21, p27, cell cycle, cyclin-dependent kinase, protein phosphorylation, protein
MEDICIN OCH VÅRD
Medical and Health Sciences
Research subject Medicine
IdentifiersURN: urn:nbn:se:uu:diva-1248ISBN: 91-554-4761-9OAI: oai:DiVA.org:uu-1248DiVA: diva2:160808
2000-10-04, Grönwallsalen, ing. 70, Akademiska sjukhuset, Uppsala, 13:15