P006 Loss of protein tyrosine phosphatase non-receptor type 23 (PTPN23) in intestinal epithelial cells induces inflammation and epithelial hyperproliferation
A. Montalban-Arques1, C. Gottier1, I. Olivares-Rivas1, M. Scharl1,2, M. Spalinger1
1University Hospital Zurich/ University of Zurich, Gastroenterology and Hepatology, Zurich, Switzerland, 2Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Colorectal carcinoma (CRC) is still a mayor complication in patients with inflammatory bowel disease (IBD) with colonic involvement. Colitis-associated cancer patients have a worse prognosis than those with spontaneous CRC, and are frequently diagnosed at an advance stage. Protein tyrosine phosphatase non-receptor type 23 (PTPN23) regulates signal transduction events involved in cell differentiation, proliferation, apoptosis, migration and invasion. Although PTPN23 is involved in some epithelial cancers, it is unknown whether PTPN23 affects intestinal epithelial cells (IEC) homeostasis and/or malignant transformation. Here we aim to identify a role for PTPN23 in the pathogenesis of IBD and CRC.
To investigate the role of PTPN23 in IBD and CRC, we generated mice specifically lacking PTPN23 in IEC. For this aim, mice homozygous for a LoxP flanked PTPN23 gene (PTPN23fl/fl), were crossed with mice heterozygous for the PTPN23fl gene expressing Cre under the Villin Promoter (PTPN23fl/WT VillinCre+/− mice). PTPN23fl/fl VillinCre+/− (KO) and control littermates were analysed at the age of 6 weeks. Additionally, PTPN23 expression was examined in patients with IBD and CRC by immunohistochemistry.
PTPN23 KO mice were born at a reduced frequency. Those that were born and did survive until weaning, were significantly smaller, featured less weight and developed severe diarrhoea. Kaplan Meier survival curve demonstrated that all of them died spontaneously within 140 days after birth. Interestingly, PTPN23 KO mice presented severe splenomegaly, but elongated small intestine and colon compared with their WT littermates. Histologically, PTPN23 KO mice showed epithelial cell hyperplasia, with an increase of Ki67+ epithelial and immune cells through the epithelium. In human, PTPN23 was highly expressed in colon tissue derived from patients with IBD and CRC primary tumours compared with healthy regions from the same patients. Aside from high expression in cancerous epithelial cells, we also observed high PTPN23 staining in immune cells within the lamina propria, indicating an important role for PTPN23 in haematopoietic cells as well. In contrast to primary CRC tissue, PTPN23 expression was almost completely lost in liver and lung metastases of the same CRC patients.
Our results suggest that PTPN23 plays an important role in IEC proliferation and inflammation. The development of this novel mouse model lacking PTPN23 specifically in IEC will allow unravelling mechanism involved in intestinal inflammation and cancer. Given the strong inflammatory phenotype observed in mice lacking PTPN23 in IEC, PTPN23 represents an interesting target in the treatment of IBD and CRC.