| Background and PurposeColorectal caner(CRC)is the third most common cancer and the fourth leading cause of cancer death in the world.High occurrence rate,inconspicuous early symptoms and high mortality rate were its significant clinical features.Therefore,it is of great importance to find new biological therapeutic targets for colorectal cancer.Microsatellite Instability(MSI)is caused by shift mutation of gene DNA pairing due to functional defects of Mismatch Repair(MMR)system,which leads to genomic instability.It is divided into microsatellite instability high-frequency(MSI-H),microsatellite instability low-frequency(MSI-L)and microsatellite stability(MSS).In recent years,MSI has become the basis for conventional treatment stratification of colorectal cancer and an indicator for evaluating the prognosis of immune checkpoint treatment.Zymogen granule protein 16(ZG16p)is a soluble high alkali protein found in rat pancreatic zymogen granules,which can be detected in intestinal goblet cells,pancreatic acinar cells,parotid gland serous acinar cells and serum.With the lectin-like domain,ZG16 participates in intestinal immune system through identification of pathogenic bacteria,stimulate T cells and participate in identification and inhibition of tumor cells.Our previous studies showed that ZG16 expression was significantly down-regulated in human colorectal cancer tissues compared with paired normal tissues.It is closely related to the therapeutic and prognosis of colorectal cancer.ZG16 and MSI have common effects on immune microenvironment regulation mutation burden of colon cancer.Further,upon the common molecular features of ZG16and MSI,we would like to find the potential prognostic role of ZG16 in the check point immunotherapy and clinical prognosis.Our previous studies have found that high expression of ZG16 was associated with the longer progression-free survival(PFS)and overall survival(OS)of colorectal cancer patients.At the same time,the preliminary results from Cancer Genome Atlas(TCGA)database indicated that the expression of ZG16 in colorectal cancer in Caucasian population is closely related to MSI,but it has not been fully clarified and scientifically explained.Therefore,in this study,the samples of colorectal cancer patients from Chinese Han population were collected and the expression levels of ZG16 were detected by real-time fluorescence quantitative PCR.The MSI status was determined by immunohistochemistry and capillary electrophoresis PCR way.The association between the ZG16 and MSI status,as well as their common clinical pathological parameters were evaluated so as to explore the potential application of ZG16 as a prognostic factor of check point immunotherapy and clinical biomarker of colorectal cancer.Methods1.MSI was detected in 400 colorectal cancer patients by capillary electrophoresis PCR and immunohistochemical staining.2.Quantitative real-time polymerase chain reaction was used to detect the relative gene expression level of ZG16 in cancer tissues and paired normal tissue.3.Statistical analysis:T test was used to analyze the ZG16 expression between MSI-H and MSI-L/MSS groups.The correlation of MSI and clinicopathological parameters were evaluated byχ~2 test and T test were used to investigate the association of ZG16 and clinicopathological parameters.The test significance difference level is a=0.05.Results1.In colorectal cancer,the relative expression level of ZGl6 in tumor tissue was significantly lower than that in paired normal tissue(P<0.05).2.Relationship between expression of ZGl6 mRNA and clinicopathological features of colorectal cancer patients:the expression level of ZGl6 mRNA in lymph node negative group is higher than that in lymph node metastasis positive group(P<0.05),the expression level of ZGl6 in non-distance metastsis patients was higher than that in distance metastasis patients(P<0.05),the expression level of ZGl6 in stageⅠ~Ⅱwas higher than that in stageⅢ~Ⅳ(P<0.05),the expression level of ZGl6 mRNA in colon tumor is relatively higher than that in rectum tumor(P<0.05),there is no significant correlation between the expression of ZGl6 mRNA and clinical features including patient’s sex,age,tumor diameter,differentiation and tumor type(P>0.05).3.MSI-H was mostly found in the group with tumor diameter nore than 5cm,and MSI-L/MSS was mostly found in the group with tumor diameter smaller than 5cm(P<0.05),MSI-H tumors occurred more in colon cancer than in rectum cancer(P<0.05),most of the MSI-H tumors showed negative lymph node metastasis,while MSI-L/MSS tumors showed positive lymph node metastasis(P<0.05),MSI-H was the most common manifestation in stageⅠ~Ⅱcolorectal cancer,and MSI-L/MSS was the most common manifestation in stageⅢ~Ⅳ(P<0.05),there was no significant correlation between MSI and clinical features of sex,age,tumor differentiation and histological type(P>0.05).4.In colorectal cancer,the relative expression level of ZGl6 in MSI-H group was significantly higher than that in MSI-L/MSS group(P<0.05).5.The expressions of MSI and ZG16 mRNA are consistent and synergistic in tumor location,lymph node metastasis,distant metastasis and clinicopathological TNM staging.Although the expression of ZG16 mRNA has no statistical significance in tumor diameter and tumor type(P>0.05),it can still be seen that the expression of ZG16mRNA is high in adenocarcinoma with tumor diameter≥5cm,which is consistent with the result that MSI-H tumors are mostly tumors with tumor diameter≥5cm.ConclusionsThe expression of ZGl6 was positively correlated with MSI in colorectal cancer,and they were synergistic in lymph node metastasis,distant metastasis,TNM staging and other clinicopathological features.ZG16 is expected to be a potential biomarker for the occurrence,development and therapeutic efficacy of colorectal cancer. |
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