Ekspresija p16, p53 i VEGF i citokinski profil u kolorektalnom karcinomu i inflamatornim bolestima creva

Abstract

Progresija od inflamacijske bolesti creva do kolorektalnog karcinoma je višestepeni proces, koji uključuje alteraciju tumor-supresorskih gena, kao što su r53 i r16. Cilj ove studije bio je da ispita obrasce ekspresije r16, r53 i VEGF u ciljanom tkivu, kao i serumske vrednosti citokina (TNF-α, TGF-β, IL-4, IL-6, IL-10, IL-17, IL-27 i IFN-γ) i tumorskih markera (AFP, CA 19-9, CEA) kod ispitanika sa inflamacijskom bolešću creva i kolorektalnim karcinomom. Serumske vrednosti citokina kod ispitanika sa ulceroznim kolitisom (n=24), Kronovom bolešću (n=5) i kolorektalnim karcinomom (n=75), kao i zdravih kontrola (n=37) analizirane su ELISA tehnikom. Endoskopske biopsije uzoraka ciljanog tkiva (ulcerozni kolitis, Kronova bolest, kolorektalni karcinom) analizirane su imunohistohemijskim bojenjem na r16, r53 i VEGF. Ispitanici sa ulceroznim kolitisom i postojanjam ekstraintestinalnih manifestacija, komplikacija i pozitivne ekspresije r16, r53 i VEGF (pojedinačno) imali su više serumske vrednosti proinflamatornih citokina. Značajno veći procenat ispitanika sa kolorektalnim karcinomom imao je pozitivnu ekspresiju r16, r53 i VEGF, u odnosu na ispitanike sa inflamacijskom bolešću creva. Ispitanici sa kolorektalnim karcinomom i pozitivnom ekspresijom VEGF imali su snižene sistemske vrednosti proinflamatornog citokina IFN-γ i povišene vrednosti imunosupresivnog citokina IL-10. Relativno niske vrednosti IL-10 kod ispitanika.

Progression from ulcerative colitis (UC) toward colorectal carcinoma (CRC) is multistep process that includes gene alterations of tumor suppressor genes, such as p53 and p16. The aim of this study was to investigate the expression patterns of p16, p53 and VEGF in affected tissue and serum levels of cytokines TNF-α, IFN-γ, IL-4, IL-6, IL-10 and IL-17 in patients with UC and CRC, respectively. Serum levels of cytokine in patients with UC (n=24) and CRC (n=75) and in a healthy group (n=37) were analyzed by ELISA. Endoscopic biopsies specimens of UC and CRC were studied by immunohistochemical staining for p16, p53 and VEGF. Patients with UC with presence of extraintestinal manifestations, complications, and positive staining of p16, p53 and VEGF respectively had higher serum levels of pro-inflammatory cytokines. Higher percentage of CRC patients had positive staining of p16, p53 and VEGF. CRC patients with positive staining of VEGF had decreased systemic values of proinflammatory IFN-γ and increased values of immunosuppressive IL-10. Relatively low IL-10 in patients with severe UC is insufficient to compensate IL-6 secretion and subsequently enhanced type 1/17 immune response. In UC patients, p16 and p53 induce enhanced VEGF expression and subsequent production of pro-inflammatory TNF-α and IL-6. In CRC patients VEGF seems to have immunosuppressive role. It appears that tumor suppressor gene-VEGF axis have dual role on immune response in inflammation of UC and tumor growth and progression of CRC.