Progranulin promotes lymphangiogenesis through VEGF-C and is an independent risk factor in human esophageal cancers

Lymph node metastasis is one of the most important predictors of the prognosis for esophageal cancer (EC) patients. However, the mechanism underlying the lymph node metastasis is largely unknown. Progranulin (PGRN) is shown to be highly expressed in various types of cancers and could promote the angiogenesis and epithelial-mesenchymal transition of cancer cells in previous studies. However, the expression status of PGRN and its effects on the lymphangiogenesis in EC are largely unclear. In this study, we show for the first time that PGRN is expressed in EC tissue samples and cell lines and could promote the expression of VEGF-C in vitro, a well-known lymphangiogenesis inducer, through the putative signaling transducers p-ERK and p-AKT. Besides, increased levels of PGRN are correlated with lymph node metastasis, high levels of lymph microvessel density, and lymph vessel space invasion in tissue samples of EC patients. In addition, Cox proportional risk model shows that patients with high levels of PGRN would have 2-fold increases in 5-year mortality compared with patients with low levels of PGRN. Finally, we establish a clinically useful nomogram to predict the possibility of mortality for individual EC patients. In conclusion, PGRN may play an important role in the lymphangiogenesis through activation of VEGF-C in the EC patients.