Interferon-alpha signaling and cell cycle regulation in neuroendocrine tumors of the digestive system

Abstract: 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.