Prognostic Value Of A Novel Multi-mRNA Signature For Predicting Relapse Of Cholangiocarcinoma And The Role Of ARPC2 In Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma(CCA)is the second most common primary liver cancer worldwide,and the incidence of cholangiocarcinoma increases year after year in China.The classification based on anatomical location includes intrahepatic,perihilar,and distal cholangiocarcinoma.Among of them,the incidence of intrahepatic cholangiocarcinoma(ICC)exceeds distal cholangiocarcinoma's in China recently.CCA is prone to early metastasis and has high recurrence rate,especially,the makers for early diagnosis is scarce,therefore,the prognosis of CCA patients is advanced.Although surgery as a optimal treatment is used in clinical,the outcome of patients is still poor for high recurrence rate.Other therapy such as TACE,chemotherapy,immunity therapy also has some limitations.In a word,exploring novel therapy target is a urgent task.Tumors have their specific genetic background,which take part in the progression of tumors.Currently,gene sequencing and other methods provide us new perspective of tumor molecular level,the emergence of databases makes it easier for us to obtain a large number of sequencing results,which was used to find new tumor markers and construct prognosis model by statistical methods.High metastasis of cholangiocarcinoma is associated with poor outcome of postoperative patients,therefore,it is important for us to find new target against the metastasis of cholangiocarcinoma.There are two parts in our study about cholangiocarcinoma and intrahepatic cholangiocarcinoma.First part,we analysis the differential expression genes of cholangiocarcinoma from GEO and TCGA,and a prognosis model for predicting the relapse of cholangiocarcinoma patients is constructed by mathematical methods.Second part,we research a gene that can promote the migration and invasion of cholangiocarcinoma,which could provide a new therapeutic target for treatment of cholangiocarcinoma.Part I Prognostic value of a novel multi-m RNA signature for predicting relapse of cholangiocarcinomaCholangiocarcinoma(CCA)is an epithelial cancer and has high death and recurrence rates,current methods cannot satisfy the need of predicting cancer relapse effectively.So,we aimed at conducting a multi-m RNA signature to improve relapse prediction of CCA.We analyzed m RNA expression profiling in large CCA cohorts from Gene Expression Ominus(GEO)database(GSE76297,GSE32897,GSE26566,GSE31370,and GSE45001)and The Cancer Genome Atlas(TCGA)database.Least absolute shrinkage and selection operator(LASSO)regression model was used to established a 7-m RNA-based signature that was significantly related to the recurrence-free survival(RFS)in two test series.Based on the 7-m RNA signature,the cohort TCGA patients could be divided into high risk or low risk subgroups with significantly different RFS [p < 0.001,hazard ratio(HR): 48.886,95% confidence interval(CI): 6.226-3.837E+02].Simultaneously,the prognostic value of the 7-m RNA signature was confirmed in clinical samples of Ren Ji hospital(p < 0.001,HR: 4.558,95% CI: 1.829-11.357).Further analysis including multivariable and sub-group analyses revealed that the 7-m RNA signature was an independent prognostic value for recurrence of patients with CCA.In conclusion,our results might provide an efficient tool for relapse prediction and were beneficial to individualized management for CCA patients.Part II The role of ARPC2 in intrahepatic cholangiocarcinomaIntrahepatic cholangiocarcinoma(ICC)is prone to lymphatic and distant metastases,which correlated to poor prognosis,current therapy cannot satisfy the need of ICC treatment.So,identifying a novel therapeutic target for ICC is urgently required.Actin-related protein 2/3 complex subunit 2(ARPC2)is an actin-binding component involved in the regulation of actin polymerization,and has been reported to promote cancer migration and invasion,but its role in ICC is obscure.In this study,we identify that ARPC2 is upregulated in human ICC tissues compared with matched normal tissues and associated with poor outcomes.Functional studies verify that ARPC2 promote migration and metastasis in cholangiocarcinoma both in vitro and in vivo.Mechanistically,ARPC2 can promote the polymerization of F-action,which is essential for lamellipodia formation.Moreover,tumor-environment play a vital role in ICC progression and can upregulated the level of ARPC2.Therefore,our results show that ARPC2 could promote the metastasis of ICC by stimulating the polymerization of F-action and could serve as a novel therapy in intrahepatic cholangiocarcinoma.