Type 4 phosphodiesterases: a possible role in hepatocyte transformation

Type 4 phosphodiesterases (PDE4) constitute a major class of hydrolases involved in modulation of intracellular signaling pathways mediated by cAMP, an important intracellular second messenger with key cellular functions, including cell proliferation, differentiation and survival. Expressed in most human tissues and abundant in liver, PDE4 has been proposed as a therapeutic target for a variety of human tumors, while the role in liver tumorigenesis remains to be defined (1). With the aim of shedding light on the role of PDE4 in hepatocyte transformation and survival, as well as on liver tumor aggressiveness, cAMP levels and cAMP-PDE activity were measured in hepatocellular carcinoma cell lines (HCC) of different origin (HepG2, Hep3B and Huh7.5) and in the terminally differentiated cell line HepaRG. Rapidly proliferating HCC cells (Hep3B and Huh7.5) exhibit significantly decreased levels of total cAMP and elevated PDE activity, PDE4 in particular. Western blot analysis using antibodies specific for the different PDE4 isoforms (A, B, C and D) showed highly increased levels of PDE4A and PDE4D proteins in Hep3B and Huh7.5 cells, compared to the less tumorigenic HepG2 and HepaRG, with major changes found in the higher MW splicing variants of both isoforms. These data indicated a connection between expression of PDE4A and PDE4D isoforms and the degree of tumor aggressiveness. SiRNA-mediated silencing of PDE4D expression appreciably slowed HCC growth through differential modulation of molecules with a key role in cell cycle progression and survival. RNAi experiments for silencing of the PDE4A gene are currently underway to investigate in addition the role of PDE4A overexpression in hepatocyte growth, thus providing a more inclusive depiction of type 4 phosphodiesterase role in hepatocyte transformation and tumorigenesis. 1. Massimi M et al. J Cell Biochem 2017, 118:1401–1411.