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* = Presenting author

P103 Evaluation of efficacy of new vectors for siRNA CYCLIN D1 and E2F1 delivery in control of cancer progression in inflammatory bowel disease

Russo I.*1, Bochicchio S.2, Piazza O.3, Barba A.A.2, Lamberti G.4, Carrizzo A.5, Zeppa P.6, Vecchione C.6, Iovino P.6, Ciacci C.6

1University of Salerno, Department of Medicine and Surgery, Baronissi Campus (Salerno), Italy 2University of Salerno, Department of Pharmacy, Fisciano, Italy 3Department of Medicine and Surgery, Department of Medicine and Surgery, Baronissi, Italy 4University of Salerno, Department of Industrial Engineering, Fisciano, Italy 5University of Salerno, Department of Medicine and Surgery, Fisciano, Italy 6University of Salerno, Department of Medicine and Surgery, Baronissi, Italy

Background

Many evidences from literature support a connection between inflammation, cancer development due to the deregulation of the cell cycle with alteration in control of the G1/S checkpoint, where Cyclin D1 (CyD1) plays a crucial role. Cyclin-dependent kinases represent critical components of the cell cycle machinery. Moreover, other studies showed that CyD1 is overexpressed in patients with IBD (inflammatory bowel disease) and some evidence indicate also that another factor, the E2F1 (E2 Promoter Binding Factor-1) modulates the beginning of the inflammatory disease. The aim of this study was the analysis of the CyD1 and E2F1 expression, regulation, and potential control of cell cycle progression and inflammation using an ex vivo culture model of colon explants from 4 IBD patients and 3 controls.

Methods

We investigated the ability of commercial siRNAs for CyD1 and E2F1 inhibition encapsulating them in invivofectamine and in some new nanoliposomal vectors, to enter in the colon explants with immunofluorescence assay. Colon explants were treated with or without EC-LPS (Lipopolysaccharide from Escherichia coli, 1mg/ml; 4 and/or 24hs) which stimulated the mucosal inflammation and cyclin expression. Then, we evaluated the silencing ability of siRNA toward CyD1 and E2F1 through western blot analysis.

Results

Our data demonstrated that commercial siRNAs for CyD1 and E2F1 nanoliposomal vectors were able to enter in the colon explant, without any tissue morphology and integrity alteration. Moreover, CyD1 and E2F1expression increased in colon explants treated in vitro with EC-LPS. We demonstrated also an efficient reduction of the CyD1 expression after treatment of IBD colon explants with CyD1 siRNA and E2F1 siRNA with a “patient-dependent response”.

Conclusion

Our results suggest that the silencing of CyD1 and E2F1 helped to attenuate the expression of these crucial factors and could potentially target inflammatory signals in the gut preventing the deregulation of cell cycle and consequently colon cancer progression.