| Colorectal cancer?CRC?is a globally serious public health problem.Its morbidity and mortality are gradually increasing while the incidence tends to be younger recently.And to the patients with ulcerative colitis,the incidence and mortality of CRC are higher.Abnormally elevated glucose metabolism,which is a common feature of CRC,can provide a large amount of energy for physiological activities such as proliferation.Thus,interfering with glucose metabolism is an important way for the treatment of CRC.Previous studies have shown that mannose has the same transport carrier protein as glucose,and it can interfere with the glucose metabolism of tumor cells for its anti-tumor activity.However,the research on the effect of mannose on CRC is still in its infancy,and the mechanism needs further research.Therefore,this study is intended to explore the preventive effect of mannose on the patients with high risk of colitis-associated colorectal cancer,as well as the possible mechanism and the target of glucose metabolism in CRC.The main research contents are as follows:First of all,to explore the preventive effect of mannose on colorectal tumorigenesis,the mouse model of colitis-associated colorectal tumorigenesis,induced by azomethane oxide?AOM?combined with sodium dextran sulfate?DSS?,was established.To explore the effects of mannose on the number of colorectal tumors,body weight and colon length in mice,other sugars were used as horizontal comparison.On the basis of that the dose used on mice had no obvious adverse effects,the results showed that the intervention of mannose can reduce the number and development of colorectal tumors,and reduce the levels of cellular inflammatory factors TNF-?and IL-6 in colorectal tissues of mice.Secondly,the xenograft model was established to explore the inhibitory effect of mannose on the proliferation of colorectal tumors,including the effects of mannose on tumor volume,body weight and tumor-to-body ratio in mice.Other sugars were used for horizontal comparison.On the basis of that the dose used on mice had no obvious adverse effects on mice,the results showed that the tumor volume in the mannose treatment group increased slowly,and the tumor-to-body ratio was lower at the end of the experiment compared with the model group.After that,to explore the effect of mannose on CRC,the CRC cell model,incluiding HCT116 and HT29 was established.By cell proliferation experiment,it was proved that glucose was the most important carbon source in the process of proliferation,and it was further found that mannose could significantly inhibit the proliferation of the two cell lines in DMEM complete culture medium with high glucose or low glucose?BGL to human?.The results of cytotoxicity test showed that the mannose IC50 values of the two cell lines were much higher than those used in the proliferation experiment,which were 125 mmol/L and 110 mmol/L,respectively.It was found that mannose could decrease the glucose uptake of the two cell lines by?68.40±3.43?%and?58.78±1.27?%after treatment with 25 mmol/L,for 48 h,respectively.Finally,we explored the possible target by western blotting and qPCR.The results showed that mannose could reduce the expression of glucose transporter GLUT1,which was originally highly expressed in CRC.The phenomenon was also confirmed in the mouse experiment,and the same results were obtained at the transcriptional level.Further research showed that the mRNA level of c-Myc?a transcription factor of GLUT1?was significantly down-regulated,and the down-regulation of GLUT1 expression was likely related to this.In summary,this study proved that mannose could interfere with glucose uptake and proliferation of CRC cells,and slow down colorectal tumor proliferation and attenuate colitis-associated colorectal tumorigenesis in mice,which may be related to the down-regulation of glucose transporter protein GLUT1.This study provides some theoretical references for the application of mannose in the clinical prevention of CRC. |
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