Effect Of Decorin On Fatty Acid Metabolism In Colorectal Cancer And Its Regulatory Mechanism

Colorectal cancer(CRC)is a common cancer,having a higher incidence than other cancers,and ranks the third and fourth in the world in terms of cancer incidence and mortality,respectively.The occurrence and development of colorectal cancer involves many factors,among which reprogramming of lipid metabolism is one of the metabolic changes that tumor cells make to resist adverse environment,which can improve the energy reserve of tumor cells and provide them with sufficient sources of nutrition.Decorin(DCN),as one of the important components of extracellular matrix,can inhibit the occurrence and development of colorectal cancer by interacting with various cytokines and cell membrane receptors,which is of great significance in clinical medicine.However,as a tumor suppressor,the effects of DCN on lipid metabolism in tumor cells and its regulatory mechanism are rarely reported.This study further explored the mechanism of the influence of DCN on the occurrence and development of colorectal cancer from the perspective of lipid metabolism.The results are as follows:1.Bioinformatics analysis showed that DCN was significantly correlated with fatty acid oxidation pathways.Data of 473 colorectal Cancer samples and 41 paracancer samples were obtained from The Cancer Genome Atlas(TCGA)database.Bioinformatics methods such as pathway enrichment analysis,differential gene expression analysis and ZDOCK protein docking were used to explore the correlation between DCN and lipid metabolism in colorectal cancer.The results showed that lipid metabolism-related pathways,including lipoic acid metabolism,oligosaccharide-lipid intermediate biosynthesis,cholesterol biosynthesis and mitochondrial fatty acid oxidation pathway,were significantly enriched in colorectal cancer patients with low DCN expression.The expression of DCN was negatively correlated with ECHS1,a key gene of fatty acid oxidation pathway,in colorectal cancer patients at all stages.In addition,the analysis results based on ZDOCK protein docking software show that there may be interaction between DCN and ECHS1 protein structures.2.In colorectal cancer cells,DCN promotes the occurrence of fatty acid oxidation pathway.Firstly,200 μ-MPA oleic acid was used to stimulate colorectal cancer cells Caco-2 to produce lipid toxicity.The effects of the addition of recombinant DCN protein on lipid metabolism were detected by oil red staining and quantitative triglyceride.The results showed that the addition of recombinant DCN protein increased the content of lipid in the cells.Secondly,the effects of the addition of recombinant DCN protein on the factors related to fatty acid metabolism were detected by RT-q PCR.The results showed that the expressions of FASN,SREBP-1C and SREBP-2 fatty acid synthesis genes were significantly decreased by DCN,while the expressions of CPT-1α and ECHS1 fatty acid oxidation genes were significantly up-regulated.Finally,Caco-2 cells were transfected with DCN overexpression plasmid,and Western blot was used to detect the influence of overexpression of DCN on fatty acid metabolism related factors.The results showed that overexpression of DCN could significantly up-regulate the expression level of AMPK and ECHS1,and significantly down-regulate the expression level of AKT.In order to promote the fatty acid oxidation catabolic pathway of colorectal cancer cells.3.Fatty acid oxidation pathways are inhibited in colorectal cancer mice with DCN deletion.We further investigated the relationship between DCN and fatty acid metabolism in vivo.Wild type and DCN knockout type mice were given a single intraperitoneal injection of AOM on the first day of modeling and normal drinking water for a week.Then,DSS was given drinking water for a week,and then replaced with normal drinking water for two weeks,which was a cycle.After three consecutive cycles,normal drinking water was given until 21 weeks to complete the establishment of the colorectal cancer mouse model.Immunohistochemical staining and RT-q PCR were used to detect the changes of fatty acid metabolism in colorectal cancer mice with DCN deletion.The results showed that the immunohistochemical staining intensity of ECHS1 decreased significantly in colorectal cancer mice with DCN deletion,indicating that DCN deletion would lead to decreased ECHS1 expression.RT-q PCR results showed that the expression of fatty acid synthesis-related genes SREBP-1C was significantly increased in colorectal cancer mice with DCN deletion,and the expression of fatty acid oxidation-related genes PPARA and ACOX-1 was significantly down-regulated.The expression of AMPK was significantly downregulated.It is suggested that the deletion of DCN inhibits the progression of fatty acid oxidation pathway in colorectal cancer mice.In conclusion,this study explored the effect of DCN on fatty acid metabolism in colorectal cancer and its potential mechanism through bioinformatics analysis and in vitro and in vivo experiments.It was found for the first time that DCN can enhance the fatty acid oxidation pathway.The regulatory mechanism may be that DCN promotes the expression of ECHS1 by up-regulating AMPK,thus enhancing the fatty acid oxidation pathway and affecting the effective utilization and storage of fatty acids in colorectal cancer cells.From a new perspective of fatty acid metabolism,this paper provides a new idea for the mechanism of core proteoglycans inhibiting the occurrence and development of colorectal cancer,and provides a rationale for the treatment and prevention of colorectal cancer with DCN...