Inflammation is an established risk factor for colorectal cancer. We and others have shown that colorectal cancer patients with elevated cysteinyl leukotriene receptor 2 (CysLT₂R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT₂R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C₄ (LTC₄)-induced differentiation in colon cancer via CysLT₂R signalling. Here, we investigated the involvement of Hedgehog (Hh)–GLI1 signalling, which is often hyperactivated in colorectal cancer. We found that the majority of colorectal cancer patients had high-GLI1 expression, which was negatively correlated with CysLT₂R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC₄-induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC₄-induced increase in differentiation markers and reduction in Wnt targets remained unaltered in GLI1-knockdown cells. The restoration of GLI1 in 15-PGDH-knockdown cells did not ameliorate the LTC₄-induced effects, indicating the importance of both 15-PGDH and GLI1. LTC₄-mediated reduction in the DCLK1 and LGR5 stemness markers in colonospheres was abolished in cells lacking 15-PGDH or GLI1. Both DCLK1 and LGR5 were highly increased in tumour tissue compared with the matched controls. Reduced Mucin-2 levels were observed both in zebrafish xenografts with GLI1-knockdown cells and in the cysltr2^−/− colitis-associated colon cancer (CAC) mouse model. Furthermore, GLI1 expression was positively correlated with stemness and negatively correlated with differentiation in CRC patients when comparing tumour and mucosal tissues. In conclusion, restoring 15-PGDH expression via CysLT₂R activation might benefit colorectal cancer patients.

炎症是结直肠癌的既定危险因素。我们和其他人已表明，具有高半胱氨酸白三烯受体2（CysLT ₂ R）和15-羟基前列腺素脱氢酶（15-PGDH）水平的大肠癌患者预后良好。然而，CysLT ₂ R和15-PGDH都起着抑癌作用，在结直肠癌中常常被抑制。我们先前曾报道，白三烯C ₄（LTC ₄）通过CysLT ₂诱导结肠癌分化R信令。在这里，我们研究了刺猬（Hh）–GLI1信号的参与，该信号在结直肠癌中常常被过度激活。我们发现大多数结直肠癌患者具有高GLI1表达，与低GLI1组相比，与CysLT ₂ R，15-PGDH和Mucin-2以及整体生存率呈负相关。LTC ₄诱导的15-PGDH以蛋白激酶A（PKA）依赖性方式下调GLI1的mRNA和蛋白表达。有趣的是，LTC ₄诱导的分化标志物增加和Wnt靶点减少在GLI1敲低细胞中保持不变。15-PGDH敲低细胞中GLI1的恢复不能改善LTC ₄诱导的效应，表明15-PGDH和GLI1的重要性。在缺乏15-PGDH或GLI1的细胞中，结肠细胞中LTC ₄介导的DCLK1和LGR5干性标记的减少被消除。与匹配的对照相比，DCLK1和LGR5在肿瘤组织中均高度增加。在具有GLI1基因敲低细胞的斑马鱼异种移植物和与cysltr2 ^-/-结肠炎相关的结肠癌（CAC）小鼠模型中，均观察到Mucin -2水平降低。此外，在比较肿瘤和粘膜组织时，CRC患者的GLI1表达与干性呈正相关，与分化呈负相关。总之，通过CysLT ₂恢复15-PGDH表达R激活可能有益于结直肠癌患者。