Colorectal cancer (CRC) severely threatens human health and life span. An effective therapeutic strategy has not been established because we do not clearly know its pathogenesis. Here, we report that ceramide and sterol O-acyltransferase 1 (SOAT1) have roles in both spontaneous and chemical-induced intestinal cancers. We first found that miRNA-148a deficiency dramatically increased mouse gut dysbiosis through upregulating ceramide synthase 5 (Cers5) expression, which promoted ceramide synthesis afterward. The newly generated ceramide further promoted both azoxymethane/dextran sodium sulfate–induced (AOM/DSS-induced) and Apc^Min/+ spontaneous intestinal tumorigenesis via increasing mouse gut dysbiosis. Meanwhile, increased level of ceramide correlated with the significant enhancements of both β-catenin activity and colorectal tumorigenesis in a TLR4-dependent fashion. Next, we found a direct binding of β-catenin to SOAT1 promoter to activate transcriptional expression of SOAT1, which further induced cholesterol esterification and colorectal tumorigenesis. In human patients with CRC, the same CERS5/TLR4/β-catenin/SOAT1 axis was also found to be dysregulated. Finally, the SOAT1 inhibitor (avasimibe) showed significant levels of therapeutic effects on both AOM/DSS-induced and Apc^Min/+ spontaneous intestinal cancer. Our study clarified that ceramide promoted CRC development through increasing gut dysbiosis, further resulting in the increase of cholesterol esterification in a SOAT1-dependent way. Treatment with avasimibe to specifically decrease cholesterol esterification could be considered as a clinical strategy for effective CRC therapy in a future study.

中文翻译：

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神经酰胺介导的肠道菌群失调增强胆固醇酯化并促进小鼠结直肠肿瘤的发生

结直肠癌 (CRC) 严重威胁人类健康和寿命。由于我们不清楚其发病机制，因此尚未建立有效的治疗策略。在这里，我们报告神经酰胺和甾醇O-酰基转移酶 1 (SOAT1) 在自发性和化学诱导的肠癌中都有作用。我们首先发现 miRNA-148a 缺乏会通过上调神经酰胺合酶 5 (Cers5) 的表达来显着增加小鼠肠道菌群失调，进而促进神经酰胺的合成。新生成的神经酰胺进一步促进偶氮甲烷/葡聚糖硫酸钠诱导（AOM/DSS诱导）和Apc ^Min/+通过增加小鼠肠道菌群失调导致自发性肠道肿瘤发生。同时，神经酰胺水平的增加与 β-连环蛋白活性和结直肠肿瘤发生的显着增强相关，且呈 TLR4 依赖性。接下来，我们发现 β-catenin 与SOAT1启动子直接结合以激活SOAT1的转录表达，从而进一步诱导胆固醇酯化和结直肠肿瘤发生。在患有 CRC 的人类患者中，还发现相同的 CERS5/TLR4/ β-连环蛋白/SOAT1 轴失调。最后，SOAT1 抑制剂 (avasimibe) 对 AOM/DSS 诱导和Apc ^{Min/+均显示出显着水平的治疗效果}自发性肠癌。我们的研究阐明，神经酰胺通过增加肠道菌群失调促进结直肠癌的发展，进一步导致以 SOAT1 依赖性方式增加胆固醇酯化。在未来的研究中，使用阿伐西贝治疗以特异性降低胆固醇酯化可被视为有效 CRC 治疗的临床策略。