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.

溃疡性结肠炎相关性结直肠癌 (UC-CRC) 是溃疡性结肠炎 (UC) 最严重的并发症。活化 T 细胞核因子 3 (NFATc3) 参与炎症和癌症。在这项研究中，我们研究了 NFATc3在体内和体外对实验性 UC-CRC 的影响，并探索了潜在的机制。在 C57BL/6 小鼠中施用氧化偶氮甲烷 (AOM) 和葡聚糖硫酸钠 (DSS) 可诱导 UC-CRC 模型。每周监测体重。在第 14 周收获结肠组织。我们检查了结肠组织中组织病理学、炎性细胞因子、致癌因子和上皮间质转化 (EMT) 标志物的变化。我们发现与对照相比，AOM/DSS 处理的小鼠中 NFATc3 的表达显着上调。缺乏 NFATc3 的小鼠显示肿瘤数量和大小减少，粘膜损伤减少，存活率增加。此外，下调 NFATc3 可以抑制 UC-CRC 的增殖和 EMT，降低促炎细胞因子的水平，减少中性粒细胞和巨噬细胞对结肠的浸润，. 在体外实验中，沉默 NFATc3 抑制了 CRC 细胞的增殖和 EMT，并降低了 P38 和 JNK 的活化。此外，miR-370-3p 可以与 NFATc3 结合。miR-370-3p 的下调促进了 CRC 细胞的增殖和 EMT，而沉默 NFATc3 可以逆转这些影响。总之，NFATc3 参与了实验性 UC-CRC 的发病机制，并且 NFATc3 敲低通过抑制炎症反应和 EMT改善了实验性 UC-CRC 的进展。NFATc3 介导 miR-370-3p 对 CRC 细胞增殖和 EMT 的抑制作用。靶向 NFATc3 可能有效治疗 UC-CRC。