Neuropilin-1 Promotes Primary Liver Cancer Progression by Potentiating the Activity of Hepatic Stellate Cells

As a co-receptor for a variety of cytokines, neuropilin-1 (NRP-1) is detectable in primary liver cancer (PLC) cells. Previous studies determined that silencing of NRP-1 expression attenuated the proliferation, migration and invasion of PLC cells. An increasing number of studies have highlighted the crucial role of the tumor microenvironment in the pathogenesis of cancer. Hepatic stellate cells (HSCs) are one of the major interstitial cell types present in the liver tumor microenvironment, and can promote the proliferation, migration and invasion of PLC cells. It remains unknown whether NRP-1 can promote PLC progression by potentiating the activity of HSCs. In the present study, the expression of NRP-1, and its co-expression with platelet-derived growth factor receptor-β, in HSCs was detected via immunofluorescence. LX2 HSCs were transfected with NRP-1 short hairpin RNA lentiviral vectors and their proliferation was observed. The proliferation, migration and invasion of HepG2 cells co-cultured with LX2 cells were also observed. Finally, LX2 and HepG2 cells were co-injected into nude mice as subcutaneous xenografts, and the tumor growth and α-smooth muscle actin expression levels were observed. NRP-1 knockdown attenuated LX2 cell activation, with concomitant downregulation of HepG2 cell proliferation, migration and invasion (P<0.05). Thus, silencing of NRP-1 expression may inhibit the activation of HSCs, as well as the proliferation, migration and invasion of PLC cells. The mechanism underlying the inhibition of PLC cell progression is possibly mediated by the inhibition of HSC activation, reduction of transforming growth factor-β1 levels in the conditioned medium and downregulation of extracellular signal-related kinase activity in PLC cells. Thus, NRP-1 could be regarded as a potential gene therapy target for PLC.