P077 SMAD7 shows a biphasic expression pattern during progression of ulcerative colitis-associated colorectal cancer
P. Chandrasinghe*1,2,3, B. Cereser2, M. Moorghen4, P. Spaggiari5, A. Maroli5, L. Del Bel Belluz2, A. Hart6, A. Spinelli5,7, J. Stebbing2, J. Warusavitarne1
1St Mark's Hospital, Department of Colorectal Surgery, London, UK, 2Imperial College London, Department of Surgery and Cancer, London, UK, 3University of Kelaniya, Department of Surgery, Kelaniya, Sri Lanka, 4St Mark's Hospital, Department of Pathology, London, UK, 5Humanitas Clinical and Research Center, Division of Colon and Rectal Surgery, Milan, Italy, 6St Mark's Hospital, Department of Gastroenterology, London, UK, 7Humanitas University, Department of Biomedical Sciences, Milan, Italy
Ulcerative colitis (UC) is an idiopathic inflammation of the intestine with an increased risk of developing colitis-associated cancer (CAC). Currently, clinical trials are underway aiming to inhibit SMAD7 to ameliorate inflammation. While the direct effect of depleting SMAD7, an inhibitory molecule in the transforming growth factor-β1 (TGFβ1) pathway, may be therapeutic in UC, its indirect effect on CAC development is largely unknown. TGFβ1 is known to enhance late stages of sporadic colorectal cancers (CRC), where SMAD7 is also elevated. Therefore, we hypothesise that removing inhibition of this pathway by depleting SMAD7 may also be detrimental for CAC. We therefore evaluated the expression of SMAD7 in the colonic epithelium during the inflammation associated neoplastic process to determine a possible role of SMAD7 in CAC.
The expression of SMAD7 protein and mRNA in colonic epithelia was assessed by immunohistochemistry (IHC) and
Cytoplasmic expression of SMAD7 protein is significantly higher in the inflammed epithelium compared with non-inflamed epithelium (
In our cohort of UC affected colon tissues, SMAD7 demonstrated a biphasic expression pattern along the different stages of CAC with peaks during active inflammation and cancer. The increase in SMAD7 expression during neoplastic transformation, comparable to sporadic CRC, may be a protective response of the epithelium to inhibit the effect of TGFβ1. Although inhibiting SMAD7 as a therapy for UC may remit inflammation, we hypothesise it may exacerbate CAC due to further enhancement in TGFβ1 signalling. We envisage further mechanistic studies