Published online Sep 14, 2022. doi: 10.3748/wjg.v28.i34.4993
Peer-review started: March 14, 2022
First decision: April 11, 2022
Revised: May 15, 2022
Accepted: August 22, 2022
Article in press: August 22, 2022
Published online: September 14, 2022
Oxidized low-density lipoprotein (ox-LDL), abnormally increased in the serum of patients with colorectal cancer (CRC) associated with a high-fat diet (HFD), may be one of the risk factors for CRC. Ox-LDL exerts a regulatory effect on macrophages, is associated with cancer stem cells, and may regulate CRC through the tumor microenvironment. The role of ox-LDL in CRC remains unclear. It is essential to explore the function of ox-LDL to explore the pathogenesis of HFD associated CRC.
The expression of ox-LDL in human colorectal cancerous tissues and colorectal tissues of hyperlipidemic mice was detected, and the function of ox-LDL in the macrophages in the tumor microenvironment was explored. Our key point is that ox-LDL up-regulates CD44 and CD133 in HFD associated CRC, which is mediated by macrophages. Our study will provide a new idea for the mechanism of HFD associated CRC.
The study aimed to investigate the role of ox-LDL through macrophage in HFD associated CRC.
The expression of ox-LDL and CD206 was detected in colorectal tissues of CRC patients with hyperlipidemia and HFD-fed mice by immunofluorescence. We stimulated macrophages with 20 ug/mL ox-LDL and assessed the expression levels of CD206 and cytokines by cell fluorescence and quantitative polymerase chain reaction. We further knocked down LOX-1, the surface receptor of ox-LDL, to confirm the function of ox-LDL in macrophages. Then, LoVo cells were co-cultured with the stimulated macrophages to analyze the CD44 and CD133 expression by western blot.
The expression of ox-LDL and CD206 was significantly increased in the stroma of colorectal tissues of CRC patients with hyperlipidemia, and also upregulated in the HFD-fed mice. Moreover, an increased level of CD206 and decreased level of inducible nitric oxide synthase were observed in macrophages after the continuous stimulation of ox-LDL. Such effects were inhibited when the surface receptor LOX-1 was knocked down in macrophages. Ox-LDL could induce CD206+ macrophages, which resulted in high expression of CD44 and CD133 in co-cultured LoVo cells.
Our study found that HFD could induce ox-LDL accumulation in CRC tissue, suggesting the regulatory role of ox-LDL in the microenvironment of CRC. Continuous stimulation of macrophages with ox-LDL induced CD206+ macrophages, which could further promote the increase of CD44 and CD133 levels in CRC cells.
Our future study will collect more samples. We look forward to make a convincing analysis to identify the correlation between ox-LDL and progression and survival of the enrolled patients in the near future. We will explore the potential signal pathways related to ox-LDL promoting M2-type macrophages by using the technology of single cell sequencing and/or RNA-Seq assay. We are confident that it will provide exciting data in the near future.