HuR/miR-124-3p/VDR complex bridges lipid metabolism and tumor development in colorectal cancer

Abstract

AbstractBackground:Maintaining lipid homeostasis to prevent lipotoxicity is crucial for various tumors, including colorectal cancer (CRC). Hu-antigen R (HuR) is a member of the RNA binding protein family and overexpressed in many cancer types, which implicted that in regulating cell proleferation, migration, invasion, and lipid metabolism. However, the role of HuR in regulating abnormal lipid metabolism of CRC is unknown.Methods:Western blot was performed to screen differentially expressed HuR between CRC tissues and adjacent normal tissues. Lipidomic profiling, RNA sequencing (RNA-seq), Cell Counting Kit-8 (CCK-8), total cholesterol and triglycerides assays testified the critical role of HuR/miR-124-3p/VDR complex in CRC cells. RNA pull-down and luciferase reporter Assays were performed to verify the interaction between HuR protein and the VDR mRNA. We also conducted a mouse xenograft model to elucidate the effect of HuR on lipid homeostasis and proliferation in vivo.Results:Our study identified that HuR promotes the expression of VDR, then modulates lipid homeostasis by enhancing TG and TC levels in CRC. Here, our study demonstrated that overexpressing HuR enhanced the expression of VDR through directly binding to its CDS and 3’-UTR. Simultaneously, HuR also indirectly affecting VDR by inhibiting miR-124-3p. We identified that HuR can suppress the expression of miR-124-3p, while miR-124-3p can bind to 3’-UTR of VDR to inhibit the expression of VDR. Moreover, xenograft models showed that targeting HuR suppressed the expression of VDR, blocked TG and TC formation, then suppressed CRC growth.Conclusion:Our findings propose a regulatory connection between HuR, miR-124-3p and VDR in CRC cells. We suggested that HuR/miR-124-3p/VDR complex modulates lipid homeostasis by influencing TG and TC formation in CRC, and may provide a potential target for CRC treatment and prevention.