Correlation Between Lymphangiogenesis And Autophagy-related Protein Beclin-1 And Hepatocellular Carcinoma

Objective(1)We conducted a meta-analysis to clarify the difference of Beclin-1 expression in HCC tissue and non-tumor liver tissue,as well as the prognostic value of Beclin-1 and its correlation with clinical pathological parameters in HCC.(2)This study was aimed to evaluate the distribution and expression of lymphatic vessel marked by D2-40 in hepatocellular carcinoma(HCC)and liver cirrhosis,and calculate lymphatic vessel density(LVD);meanwhile to compare the difference of LVD in different types of liver tissues and explore the relationship between LVD and HCC clinicopathological features and prognosis;the correlation between LVD and autophagy-related protein Beclin-1 expression was also analyzed.Methods(1)A systematic literature search was performed in Pub Med,EMBASE,China National Knowledge Infrastructure(CNKI),Wan Fang and Chinese VIP databases before October 1,2017.The included literatures were determined based on the inclusion and exclusion criteria.Newcastle-Ottawa-Scale(NOS)was used to evaluate the quality of the eligible literatures.Pooled odds ratios(ORs)with 95% confidence intervals(CIs)were used to evaluate the association of Beclin-1 expression with different type liver tissues and clinicopathological characteristics.Hazard ratio(HR)with 95% CI was combined to estimate the impact of Beclin-1 expression on prognosis of HCC.(2)Lymphatic vessels were detected immunohistochemically using monoclonal antibody D2-40 in 60 cases of HCC(including intratumoral tissue and peritumoral tissue)and 20 cases of liver cirrhosis tissues;moreover,the expression of Beclin-1 in HCC was explored.Results(1)A total of 10 high-quality articles,consisting of 8 English articles and 2 Chinese articles,with 1086 HCC patients were enrolled in our analysis.Meta-analysis results showed that(1)there was no significant difference of Beclin-1 expression between HCC and non-tumor liver tissue(HCC vs.non-tumor liver tissue: OR=2.48,95%CI= 0.64-9.58,P=0.19);(2)low expression of Beclin-1 in HCC was significantly associated with histological grade(poor-undifferentiated vs.well-moderate: OR=2.34,95% CI= 1.65-3.32,P<0.00001);(3)low expression of Beclin-1 in HCC was associated with poor overall survival(OS)(HR=1.43,95% CI=1.17-1.75,P=0.0004).(2)(1)The positive rate of D2-40 in intratumoral tissue,peritumoral tissue and liver cirrhosis tissue was 65.0%(39/60),98.3%(59/60)and 90.0%(18/20)respectively,and lymphatic vessels marked by D2-40 positive mainly distributed in the peritumoral area.(2)Peritumoral LVD was significantly higher than that in intratumoral area(P=0.000)and liver cirrhosis tissue(P=0.000).LVD in liver cirrhosis tissue was also higher than intratumoral LVD(P=0.023).(3)HCC LVD was associated with TNM stage(P=0.012).(4)The disease-free survival(DFS)rate and 5-overall survival(5-OS)rate in 60 HCC patients were 30.0%(18/60)and 46.7%(28/60)respectively.(5)Kaplan-Meier(K-M)survival curve showed that LVD high expression negatively associated with DFS(P=0.017),but not 5-OS(P=0.162).(6)Univariate survival analysis showed that DFS was associated with tumor size(P=0.009),vascular invasion(P=0.021),TNM stage(P=0.017)and LVD(P=0.017);5-OS was associated with tumor size(P=0.009)and TNM stage(P=0.026).(7)Multivariate survival analysis showed that tumor size(P=0.012)and LVD(P=0.021)were independent predictors of DFS,and tumor size was only an independent prognostic factor for 5-OS(P=0.012).(8)The positive expression rate of Beclin-1 was 63.3%(38/60)in HCC.Some association of Beclin-1 expression with LVD was indicated but it failed to reach statistical significance(P=0.080).Conclusions(1)low Beclin-1 expression may relate to poor differentiation and unfavorable prognosis in HCC.(2)lymphangiogenesis was found in the occurrence and development of HCC,and mainly occurs in peritumoral region;the high expression of LVD may promote the recrudescence and metastasis of HCC,and accelerate the progression of HCC,which cause unfavorable outcome.