The Role And Mechanisms Of Low Density Lipoprotein Cholesterol In Intestinal Tumor Initiation And Progression

ObjectiveDiet and obesity play an important role in cancer development.Elevated serum cholesterol levels have been shown to be linked to a higher risk of colorectal adenoma and colorectal cancer(CRC).However,the effect of cholesterol on metastasis in CRC has not been widely studied,and the mechanisms by which cholesterol regulates CRC remain unclear.The current study further explored the role and mechanisms of low density lipoprotein cholesterol in intestinal tumor initiation and progression.Materials and Methodswe performed cohort studies comprising CRC patients to explore the effects of cholesterol and the LDL receptor(LDLR)on cancer progression,and in vivo and in vitro experiments to assess the effects of LDL on CRC tumorigenicity,growth,migration and stemness.Furthermore,the association between LDL and ROS/the MAPK pathway was also evaluated by DCFH-DA fluorescence analysis and Whole Human Genome Microarray.ResultsElevated LDL levels in CRC patients with liver metastases.LDL promotes CRC cell sternness in vitro.HFD promotes xenograft tumor growth.HFD potentially promotes CRC tumorigenesis.LDLR expression levels are upregulated and associated with progression in CRC.LDL causes elevated ROS levels and activates the MAPK pathway.ConclusionLow density lipoprotein cholesterol enhances intestinal tumorigenicity and tumor progression via ROS elevation and MAPK signaling pathway activation.The study provides a better understanding of the mechanisms by which LDL regulates CRC and indicates that strategies that act by lowering cholesterol may be helpful in reducing CRC risk and could be used as potential adjunctive therapies for CRC.