High Expression of PC4 is Associate With Lymphatic Metastasis and Predicts Poor Prognosis in Lung Adenocarcinoma Probably via CCR7/VEGF-C/VEGFR-3 Cascade

Abstract Purpose: PC4 is a novel marker for diagnosis and treatment of advanced human cancers metastasis. This study aimed to verify that high expression of PC4 is associated with lymphatic metastasis and predicts poor prognosis in lung adenocarcinoma probably via CCR7/VEGF-C/VEGFR-3 cascade.Methods: PC4 protein expressions in 96 lung adenocarcinoma cases, CCR7/VEGF-C/VEGFR-3 protein expressions in 23 lung adenocarcinoma cases, and PC4 clinical outcome in 83 lung adenocarcinoma cases and TCGA as validation were evaluated, respectively. Small interfering RNA was used to explore the relationship of PC4 and the VEGF-C/VEGF-D/VEGFR-3 axis in A549 cells. The correlations between PC4 and CCR7, CCR7 and VEGF-C/VEGFR-3 were analyzed in A549 cells and adenocarcinoma tissues, respectively.Results: The results shown PC4 protein highly expressed in tumor tissue compared with normal lung tissue. High expressions of PC4 were remarkably associated with advanced tumor stage (P=0.032), lymphatic metastasis (P=0.004) and poor clinical outcomes (the cohort: HR: 2.135, 95% CI: 1.279-3.562; TCGA: HR: 2.983, 95% CI: 1.249-7.127) in lung adenocarcinoma. CCR7 expressions were remarkably decreased after PC4 RNAi in A549 cells, and significantly correlated with the expressions of VEGF-C and VEGFR-3 in adenocarcinoma tissues.Conclusion: CCR7/VEGF-C/VEGFR-3 expressions in lung adenocarcinoma were closely associated with lymphatic metastasis. Overexpression of PC4 is a predictor of lymphatic metastasis and poor prognosis in lung adenocarcinoma. PC4 plays important oncogenic roles probably via activation of CCR7/VEGF-C/VEGFR-3, which warrants further study.