Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition

Ulcerative colitis-associated colorectal cancer (UC-CRC) is the most serious complication of ulcerative colitis (UC). Nuclear factor of activated T cells 3 (NFATc3) is participated in inflammation and cancer. In this study, we investigated the effects of NFATc3 on experimental UC-CRC in vivo and in vitro , and explored the underlying mechanisms. Administration of azoxymethane (AOM) and dextran sulfate sodium (DSS) induced UC-CRC model in C57BL/6 mice. Body weight was monitored weekly. Colon tissues were harvested at week 14. We examined changes in the histopathology, inflammatory cytokines, carcinogenesis factors, and epithelial-mesenchymal transition (EMT) markers in colon tissues. We found that NFATc3 expression was significantly up-regulated in AOM/DSS treated mice compared with control. Mice lacking NFATc3 showed decreased tumor number and size, decreased mucosal damage, and increased survival rate. Moreover, down-regulation of NFATc3 could inhibit the proliferation and EMT of UC-CRC, decrease the levels of pro-inflammatory cytokines, reduce the colonic infiltration by neutrophils and macrophages, and suppress the activation of P38 and JNK signal pathway in mice . In In vitro experiments, silencing NFATc3 suppressed the proliferation and EMT of CRC cells, and reduced the activation of P38 and JNK. In addition, miR-370-3p could bind to NFATc3. Down-regulation of miR-370-3p promoted proliferation and EMT of CRC cells, while silencing NFATc3 could reverse these effects. In conclusion, NFATc3 was involved in the pathogenesis of experimental UC-CRC and NFATc3 knockdown ameliorated experimental UC-CRC progression via the inhibition of inflammatory responses and EMT. NFATc3 mediated the inhibitory effects of miR-370-3p on CRC cells proliferation and EMT. Targeting NFATc3 may be effective in treating UC-CRC.