Phospholipase Cγ1 links inflammation and tumorigenesis in colitis-associated cancer.

ABSTRACT

Colorectal cancer (CRC) is the third diagnosed cancer and the second leading cause of cancer-related deaths in the United States. Colorectal cancer is linked to inflammation and phospholipase Cγ1 (PLCγ1) is associated with tumorigenesis and the development of colorectal cancer; however, evidence of mechanisms connecting them remains unclear. The tight junctions (TJ), as intercellular junctional complexes, have an important role for integrity of the epithelial barrier to regulate the cellular permeability. Here we found that PLCγ1 regulated colitis and tumorigenesis in intestinal epithelial cells (IEC). To induce the colitis-associated cancer (CAC), we used the AOM/DSS model. Mice were sacrificed at 100 days (DSS three cycles) and 120 days (DSS one cycle). In a CAC model, we showed that the deletion of PLCγ1 in IEC decreased the incidence of tumors by enhancing apoptosis and inhibiting proliferation during tumor development. Accordingly, the deletion of PLCγ1 in IEC reduced colitis-induced epithelial inflammation via inhibition of pro-inflammatory cytokines and mediators. The PLCγ1 pathway in IEC accelerated colitis-induced epithelial damage via regulation of TJ proteins. CONCLUSIONS: Our findings suggest that PLCγ1 is a critical regulator of colitis and colorectal cancer and could further help in the development of therapy for colitis-associated cancer.