Phosphodiesterase 4D Depletion/Inhibition Exerts Anti-Oncogenic Properties in Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Drug resistance is a serious problem in the treatment of HCC. Therefore, it is of high clinical impact to discover targeted therapies that may overcome drug-related resistance and improve the survival of patients affected by HCC. In the present study, we investigated the role of Isoform D of type 4 phosphodiesterase (PDE4D) in HCC development and progression. We found that PDE4D is over-expressed HCCs in vitro and in vivo and the depletion of the gene by silencing or the pharmacological inhibition of protein activity exerted anti-tumorigenic activities. ABSTRACT: Isoform D of type 4 phosphodiesterase (PDE4D) has recently been associated with several human cancer types with the exception of human hepatocellular carcinoma (HCC). Here we explored the role of PDE4D in HCC. We found that PDE4D gene/protein were over-expressed in different samples of human HCCs compared to normal livers. Accordingly, HCC cells showed higher PDE4D activity than non-tumorigenic cells, accompanied by over-expression of the PDE4D isoform. Silencing of PDE4D gene and pharmacological inhibition of protein activity by the specific inhibitor Gebr-7b reduced cell proliferation and increased apoptosis in HCC cells, with a decreased fraction of cells in S phase and a differential modulation of key regulators of cell cycle and apoptosis. PDE4D silencing/inhibition also affected the gene expression of several cancer-related genes, such as the pro-oncogenic insulin growth factor (IGF2), which is down-regulated. Finally, gene expression data, available in the CancerLivER data base, confirm that PDE4D over-expression in human HCCs correlated with an increased expression of IGF2, suggesting a new possible molecular network that requires further investigations. In conclusion, intracellular depletion/inhibition of PDE4D prevents the growth of HCC cells, displaying anti-oncogenic effects. PDE4D may thus represent a new biomarker for diagnosis and a potential adjuvant target for HCC therapy.