| Background: Cholangiocarcinoma(CCA)is a malignant tumor originating from biliary epithelial cells..According to different site,it can be divided into distal CCA,hilar CCA and intrahepatic CCA.The surgical resection is an effective treatment for early cholangiocarcinoma.However,the malignant degree of cholangiocarcinoma is high,lymph node and distant metastasis are easy to occur,especially the liver metastasis of cholangiocarcinoma is more common in clinic.Cholangiocarcinoma has a high recurrence rate after surgery and is insensitive to chemoradiotherapy,so the prognosis of patients with cholangiocarcinoma is poor.Studying the mechanism of lymph node and distant metastasis of cholangiocarcinoma,Especially the mechanism of liver metastasis of cholangiocarcinoma has certain clinical value for the diagnosis,treatment and prognosis evaluation of cholangiocarcinoma.Integrin β5 is a glycoprotein widely present on the surface of cell membranes,which specifically binds to Integrin αv to form αvβ5 and mediates mutual recognition and adhesion between cells and between cells and extracellular matrix,which is of great significance.At the same time,the expression level of Integrin β5 is abnormal in a variety of tumors,which is closely related to the lymph node and distant metastasis of tumors.For example,in pancreatic ductal adenocarcinoma,integrinβ5 mediates the specific uptake of exosomes secreted by tumor cells by Kupffer cells,thereby promoting pro-hepatic metastasis of pancreatic cancer.At present,exosome integrin β5is rarely studied in liver metastasis of cholangiocarcinoma,and the related mechanism remains unclear.Objective: We investigated the relationship between Integrin β5 and clinicopathological features of cholangiocarcinoma and the role of exosome Integrin β5in liver metastasis of cholangiocarcinoma.Methods: The pathological tissue samples of cholangiocarcinoma were selected and the integrinβ5 level was detected by immunohistochemical staining to explore the relationship between clinicopathologic features and Integrinβ5.Through the Kaplan-Meier method,the relationship between survival time and Integrinβ5 of cholangiocarcinoma patients was explored,and the survival time of cholangiocarcinoma patients after operation was analyzed by Cox model to understand the overall prognosis of cholangiocarcinoma.Western Blot and q RTPCR techniques were used to detect the expression of tumor metastasis-associated factors after tumor cells ingest QBC939 secreted by cholangiocarcinoma cells;si RNA technology was used to interfere with the expression of Integrinβ5 in the exosomes of cholangiocarcinoma cells(QBC939).Observed the changes in the uptake level of exosomes in cholangiocarcinoma cells before and after interference.Results: The results of immunohistochemical experiment showed that the expression of Integrin β5 was abnormal in cholangiocarcinoma tissues.The expression level of Integrin β5 was correlated with liver metastasis and differentiation of cholangiocarcinoma,but not with gender,age,tumor location,TNM stage,lymph node metastasis and serum CA199.The expression level of integrin β5 was higher in low differentiated cholangiocarcinoma than in moderately and well differentiated cholangiocarcinoma.Kaplan-Meier analysis showed that the average survival time of Integrin β5 high expression group was significantly shorter than that of low expression group,and the difference was statistically significant(P < 0.001).Cox single factor analysis showed that high expression of Integrin β5 was a risk factor for shortening the survival except for low differentiation and late TNM stage(HR =4.464;95 % CI1.947-10.234;P < 0.001).With the exception of TNM staging,high Integrin β5expression was an independent risk factor for shortening the survival time of cholangiocarcinoma,according to multivariate analysis(HR = 3.487;95% CI 1.349 –9.016;P = 0.010).Western Blot and PCR results showed that the expression levels of SDF-1,VEGF-A,TGF-β and other tumor metastasis-associated factors increased after Kupffer cells took up the exosomes secreted by cholangiocarcinoma cells(QBC939).The uptake capacity of Kupffer cells to QBC939 exosomes was significantly decreasing after interference of QBC939 Integrin β5.Conclusions:1.There is abnormal expression of Integrin β5 in cholangiocarcinoma tissues,and the high expression of Integrin β5 is correlated with the differentiation and liver metastasis of cholangiocarcinoma,which is a risk factor for shortened bile duct survival.2.Cholangiocarcinoma exosomes can promote the expression of tumor metastasis-associated factors such as SDF-1,VEGF-A and TGF-β in Kupffer cells.3.Changes in the expression of Integrin β5 in cholangiocarcinoma can affect the uptake of Kupffer cells into exosomes.In summary,cholangiocarcinoma cells can promote the formation of liver metastasis by altering Integrin β5 expression and guiding their secreted exosomes into Kupffer cells. |
PDF Full Text Request