| Background and objectivesThe morbidity of colon cancer was incerased in recently,and colon cancer had been one the main causes resulting for the death of cancer.Liver metastasis was the leading reason for the recurrence and death of colon cancer,and more than 60%of advanced colon cancer patients were diagnosed with liver metastasis.The progress of colon cancer was very complicate,stem cell theory persisted that only stmeness-like cell posess tumorigenesis.Cancer stem cell(CSC),different with the normal tumor cells,was a small subpopulation of cells within tumors which possessed the strong ability of self-renewal and immunotolerance.Moreover,CSC was capable of promoting malignant transformation leading to cancer progression and metastasis.In addition,CSC showed high resistance to chemotherapy and usually led to tumor recurrence.Therefore,targeting CSC was considered to be a new and effective way in treatment of tumors.The occurrence and development of tumor was not only caused by genetic mutations,but also related to epigenetic changes.Study found that hypermethylation of genes often leading to the inactivation of gene transcription and dysfuntion of cells,which will cause the happening of the disease,even tumor.It was interesting that DNA methylation was a reversible biochemical process that generated and maintained by a family of DNA methyltransferase(DNMT).It has been proved that dysregulated of DNMT expression will lead to the development of tumor.Recent studies have discovered that DNMT inhibitors had great efficacy in sustaining decreased DNA methylation and re-expression of silenced tumor suppress genes in tumor cells.In addition,these drugs were also able to reduce tumorigenicity and target CSC populations within the tumor in solid cancer.Therefore,DNMT inhibitor may become a new treatment for colon cancer.However,there was little study on the usage of DNMT inhibitors on the stem-like properties of colon cancer cell.In current study,we assessed the influence of DNMT inhibitor on the sternness of colorectal CSCs and elucidated the relevant mechanisms.Methods and resultsPart1:Here,we performed a series of experiments to investigated the influence of DNMT inhibitor 5-AzaDC on the CSC properties of colon cancer cells.Our datas suggested 5-AzaDC treatment inhibited clone formation,sphere formation and tumor invasive capacity and repressed stem-cell associated gene expression.In vivo,maintenance treatment with 5-AzaDC inhibited liver metastatic tumor growth compared to control group.Part2:In present study,we found the down-regulated expression of active ?-catenin decreased its accumulation in nucleus of colon cancer cells and reduced the protein expression level of downstream genes.Additionally,data indicated that inhibition of CSCs may associate with decreased Wnt/?-catenin signaling.TCGA database suggested that among Wnt inhibitor genes,only SFRP1 was significantly reduced in tumors compared to adjacent normal tissues and the methylation of CpG islands of SFRP1 was significantly increased in tumor samples.What's more,we confirmed that re-expression of Wnt antagonists inhibited the stemness of HCT116 cells indicating that epigenetic silence of SFRP1 contribute to colon cancer tumorigenesis.Further data indicated that re-expression of SFRP1 deregulated the Wnt/?-catenin pathway.ConclusionOur findings suggested that the epigenetic silencing of Wnt inhibitor genes was one of the reasons for the aberrant of Wnt/?-catenin signaling,was important for maintenance of CSCs within colon tumors,and DNMT inhibitor may significantly suppress the stemness of colon cancer cells and its growth in the liver.And inhibition of DNMT may be provided as a new potential therapeutic method to against advanced colon cancer in the future. |
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