University Hospital Tuebingen, Dept. for Urology, Germany
Introduction: Differential insulin receptor (IR) expression and altered ratios of IR substrate (IRS) isoforms 1 and 2 in malignant tissues suggest a potential involvement of this cascade in urothelial cancer (UC) tumor biology and pathogenesis. Patients suffering from diabetes mellitus (DM) show an increased risk of developing UC and present with impaired prognosis. As the cellular link in pathogenesis is still unclear for UC and DM, we investigated IRß, IRS1,2 and their ratio (%IRS1/2) in muscle-invasive UC compared to normal urothelial tissue and their influence on the pro-oncogenic PI3K-AKT-mTOR signaling pathway. Methods: In 103 muscle-invasive UC patients (n=31 pT2, n=72 >pT2; n=25 G2, n=78 >G2; n=23 DM) after radical cystectomy, tumor tissue was constructed to a tissue microarray and protein expression levels of IRß and of IRS1,2 were evaluated by immunohistochemistry and scored. Subsequently, expression results of these cascade proteins including their ratios were compared to expression levels of protein kinase B (AKT), each in the cytoplasm (CP) and nuclear (Nuc) compartment of UC and benign urothelium (n=42), respectively. Results: All variables IRß, %IRS1/2-CP as well as -Nuc showed significantly lower expression levels in UC, with strongly decreased IRS1 expression (all p<0.02). UC tissue from patients with DM showed significantly lower IRS2-Nuc expressions ( <0.03). Expression of IRß, IRS1,2-CP as well as -Nuc correlated with AKT in univariate analysis (all <0.0001). In multivariate analysis, IRß, IRS1-CP and IRS2-Nuc remained independently associated with AKT signaling. DM hereby modifies the relationship between IRS1-CP and AKT in UC: In patients suffering from DM, their linear association is less pronounced (m=0.01) as compared to UC patients without DM (m=0.003, interaction term p=0.039). Conclusions: The study shows significant alterations of insulin signaling in UC. The interactions of the IR cascade and protein kinase B appear individually associated with DM-associated metabolic alterations which may confer to distinct UC biology. SOURCE OF Funding: Funded by the Eberhard-Karls-University of Tuebingen and the University Hospital Tuebingen.
