Ceramide-mediated gut dysbiosis enhances cholesterol esterification and promotes colorectal tumorigenesis in mice.

Yahui Zhu,Xi Lin,Xingrong Lin,Xinyi Zhou,Yi Tang,Edward V Prochownik,Cheng Liu,Bingjun Lu,Jinmiao Zhang,Youjun Li,Li Gu

doi:10.1172/jci.insight.150607

Abstract

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 ApcMin/+ 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 ApcMin/+ 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.

Highlights

Colorectal cancer (CRC) threatens human health and lifespan, which is evidenced by that both incidence and mortality are within the top three positions among all clinically diagnosed tumors (1, 2)
Results miR-148a loss increased gut dysbiosis to enhance colorectal tumorigenesis To investigate whether miR-148a loss regulates gut microbiota disorders in AOM/DSSinduced CRC, cohousing experiments were performed to find that the susceptibility toward colitis-associated tumorigenesis was able to be transferred to the cohoused normal mice by equilibrating the gut microbiota (7-9, 13, 42)
The cohoused WT mice exhibited the opposite changes in results compared to the separately housed WT ones (Figure 1, A and B; Supplemental Figure 1, A and B). These results suggested that gut microbiota imbalance played the critical role on colorectal tumorigenesis in miR-148a-/- mice

Summary

Introduction

Colorectal cancer (CRC) threatens human health and lifespan, which is evidenced by that both incidence and mortality are within the top three positions among all clinically diagnosed tumors (1, 2). Previous studies showed that altered colonic bacterial composition affected the susceptibility to colitis and colitis associated cancers in several gene knock out (KO) animal models, such as Nlrp[6], Asc, Il18, Aim[2] and Il-33 KO mice models (8, 13, 16, 19, 20) Besides findings in these animal models, miR-148a was originally identified as the most obvious tumor suppressor in many cancers, such as CRC, liver cancer and gastric cancer (21-24). Our previous results demonstrated that the miR-148a-deficienct mice were highly susceptible to intestinal inflammation and colitis-associate tumorigenesis because of the significant inhibitions on critical regulators for both NF-κB and STAT3 signaling under pro-inflammatory environment (22) After this finding, we are still not clear that whether and how miR-148a regulates gut microbiota imbalance to contribute to colorectal tumorigenesis

Methods

Results

Conclusion