| BackgroundCholangiocarcinoma(CCA)is a malignant tumor derived from the bile duct epithelium.In the eighth edition of the 2017 American Joint Committee on Cancer(AJCC)and the Union for International Cancer Control(UICC),cholangiocarcinoma is classified as intrahepatic cholangiocarcinoma(ICC).,hieral cholangiocarcinoma(PCC)and distal cholangiocarcinoma(DCC).Different anatomical locations of cholangiocarcinoma have unique risk factors,molecular pathogenesis,treatment options,and prognosis.PHCC is the most common type of cholangiocarcinoma,accounting for more than 50%of all cholangiocarcinomas,but its clinical prognosis is the worst.Because early symptoms of hilar cholangiocarcinoma are not significant,most patients lose the opportunity for radical resection once diagnosed.At the same time,due to the complicated anatomical relationship of PHCC,radical resection is more difficult.Even in patients undergoing radical resection,the 5-year overall survival rate(OS)of PHCC was only 30%.In recent years,due to the advancement of various techniques such as preoperative diagnosis,surgical methods and postoperative care,the prognosis of PHCC patients has been improved.Many domestic experts advocate the treatment of type ? and ?hilar cholangiocarcinoma with perihepatic hiatectomy,which has achieved certain clinical effects and prolonged the survival time of some patients.However,due to the difficulty of surgical operation,high technical requirements,and long recovery time after surgery,this procedure is difficult to promote in primary hospitalsPart of the poor prognosis of PHCC is the lack of effective adjuvant therapy,its limited efficacy in chemotherapy or radiotherapy,and no targeted drugs available for the first line.Therefore,it is urgent to find new tumor markers or therapeutic targets.The Wnt signaling pathway is an essential and highly conserved molecular mechanism in many cellular basic physiological processes such as proliferation or differentiation.Abnormal activation of the Wnt signaling pathway has been observed in many types of cancers such as hepatocellular carcinoma and colorectal cancer.In 2015,Boutter et al.found that activation of the Wnt signaling pathway promotes the development of intrahepatic cholangiocarcinoma.In the canonical Wnt signaling pathway,the TCF7/?-catenin complex is a key effector complex that determines the activation of target genes downstream of the Wnt signal.Transcription factor 7(TCF7)is one of the four members of the TCF family.By binding to nuclear ?-catenin,TCF7 promotes Wnt signaling and activates transcription of target genes,thereby promoting tumor growth.Biological behavior such as invasion.Therefore,TCF7 is a key pivot molecule in the Wnt signaling pathway.However,although TCF7 is involved in the development and progression of many tumors,its expression profile and function in PHCC have not yet been elucidated.Objective1.Screening key tumor markers of PHCC and exploring new therapeutic targets2.To determine the expression of TCF7 in PHCC and compare the effect of high expression of TCF7 on the prognosis of patients3.The expression of TCF7 was detected after operation to layer the prognosis of patients with PHCC,to guide the individualized treatment and accurate treatment after operation,and to improve the quality of life of patients and prolong the survival time of patientsMethods1.Collect 5 pairs of fresh PHCC tissues and adjacent normal tissues with clear pathological diagnosis,and entrust Beijing Allwegene Gene Technology Co.,Ltd.to perform transcriptome sequencing(RNA-seq)to obtain differential gene expression profiles,that is,candidate tumor marker,was obtained.2.A total of 103 paraffin-embedded specimens of patients undergoing radical resection of PHCC from January 2012 to December 2015 in six tertiary hospitals in Shandong Province,including Qilu Hospital of Shandong University.Tissue microarrays(TMA)were made and immunohistochemical(IHC)staining was performed to verify the expression of TCF7 in tissue microarrays.The cut-off value was obtained according to the ROC curve(receiver operating characteristic curve),and then it was divided into a low expression group of TCF7(54 cases)and a high expression group of TCF7(49 cases).3.Correlation between TCF7 expression and PHCC clinicopathological factors was obtained by log-rank test.Cox regression model was used for multivariate analysis to analyze the independent prognostic significance of clinicopathological factors.This indicates that TCF7 has predictive effect on the prognosis of PHCC.4.Retrospective analysis of the patient's clinical data,through telephone follow-up or field research to understand the patient's survival.Survival analysis was performed by Kaplan-Meier method to determine the effect of TCF7 expression level on the prognosis of PHCC patients.Results1.The expression of TCF7 in cancer tissues was significantly up-regulated by transcriptome sequencing(p=0.026),indicating that TCF7 is carcinogenic in PHCC.2.Compared with the low expression group of TCF7,there was no significant difference in age,gender,TNM stage,nerve invasion and biliary calculi in the TCF7 high expression group(p>0.05).Tumor size and tumor differentiation in the TCF7 high expression group.The degree was significantly different from that of the low expression group of TCF7(p<0.05),that is,the tumor diameter of TCF7 high expression group was significantly larger than that of TCF7 low expression group(?2=5.127,p=0.024),and the degree of differentiation was lower,and the degree of malignancy of tumor was higher(?2=5.352,p=0.021).This suggests that TCF7 may be involved in tumor proliferation in PHCC.3.Univariate and multivariate analysis was used to evaluate the expression of TCF7 and the prognostic value of clinicopathological factors.The 3-year survival rate was 59.0%in patients with high expression of TCF7 and 23.0%in patients with low expression of TCF7.There was significant difference in univariate analysis(p= 0.019).The 3-year survival rate of patients without lymph node metastasis(NO)was 46.2%,and that of patients with lymph node metastasis(N1/N2)was 21.6%.There was significant difference in univariate analysis(p=0.031).The 3-year survival rate of patients with low TNM stage(?/?)was 36.4%.The 3-year survival rate of patients with high TNM stage(?/?)was 30.1%.There was significant difference in univariate analysis(p=0.014).The results showed that all three were related to the poor prognosis of PHCC.Age,tumor size,differentiation,T stage,M stage,nerve invasion and cholelithiasis were not factors affecting the prognosis of PHCC.Except for TNM stage,the prognostic factors of p>0.030 in univariate analysis were included in Cox regression model for multivariate analysis.The results showed that TCF7 was an independent prognostic biomarker of PHCC(p=0.024),while other factors could not be used as independent prognostic biomarkers(p>0.05).4.Survival analysis by Kaplan-Meier method showed that patients with high TCF7 expression had lower survival rates(p=0.019)compared with patients with low TCF7 expression,indicating that high expression of TCF7 affects the prognosis of PHCC patients,resulting in a decrease in overall survival.Conclusion1.There are differences in the expression of TCF7 in PHCC tumor tissues and paracancerous tissues,and the expression is generally high in PHCC tissues,suggesting that TCF7 can promote the occurrence and development of PHCC.2.The tumor diameter of the patients with high expression of TCF7 was significantly higher than that of low-expression patients,and the degree of tumor differentiation was generally lower and the degree of malignancy was higher.3.The expression of TCF7,lymph node metastasis and clinical TNM stage were related factors to the prognosis of PHCC patients.The high expression of TCF7,lymph node metastasis and high TNM stage suggested that the prognosis was poor.4.TCF7 is an independent factor affecting the prognosis of PHCC.The prognosis of PHCC patients with high expression of TCF7 is poor,and the overall survival rate is significantly lower than that of patients with low expression of TCF7. |
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