Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma

Abstract

Protein phosphatase 2A (PP2A) is a heterotrimeric protein phosphatase consisting of a 36-k D catalytic C subunit (PP2Ac). This study aimed to explore the prognostic and biological significance of PP2Ac in human hepatocellular carcinoma (HCC). High PP2Ac expression was significantly (P < 0.01) associated with serum hepatitis B surface antigen positivity, serum hepatitis B e antigen positivity, liver cirrhosis, moderate to poor differentiation grade, advanced disease stage, intrahepatic metastasis, and early recurrence in HCC. Multivariate analysis revealed PP2Ac as an independent prognostic factor for overall survival. Enforced expression of hepatitis B virus X protein (HBx) and its carboxyl-terminal truncated isoform induced PP2Ac expression in HCC cells. Co-immunoprecipitation assay revealed a direct interaction between PP2Ac and HBx. Small interfering RNA-mediated knockdown of PP2Ac significantly inhibited in vitro cell proliferation, colony formation, migration, and invasion and reduced tumor growth in an xenograft mouse model. In contrast, overexpression of PP2Ac promoted HCC cell proliferation, colony formation, and tumorigenesis. Additionally, silencing of PP2Ac impaired the growth-promoting effects on HepG2 HCC cells elicited by overexpression of carboxyl-terminal truncated HBx. Gene expression profiling analysis showed that PP2Ac downregulation modulated the expression of numerous genes involved in cell cycle and apoptosis regulation. Collectively, PP2Ac upregulation has a poor prognostic impact on the overall survival of HCC patients and contributes to the aggressiveness of HCC. PP2Ac may represent a potential therapeutic target for HCC.

The Hepatitis B Virus Interactome: A Comprehensive Overview

“…Several selective inhibitors (e.g., C646) for histone acetyltransferase like CBP and P300 have been used to study the inhibitory effect on HBV transcription (Tropberger et al, 2015). The prodrug GS-5801 has also been shown to inhibit transcription from cccDNA by blocking the activity of lysine demethylase 5 (KDM5) (Gilmore et al, 2017). Although these observations show that silencing of HBV transcription is possible, the main throwback of most of these targets is the lack of desired selectivity for cccDNA and their potential to impact cellular processes.…”

Synergistic Effect of MC-LR and C-Terminal Truncated HBx on HepG2 Cells and Their Effects on PP2A Mediated Downstream Target of MAPK Signaling Pathway

“…These issues need to be further explored. However, the involvement of MC-LR and ctHBx in carcinogenesis and progression is not wellunderstood, particularly with respect to regulation of PP2A enzyme activity to activate downstream MAPK signaling in hepatocellular carcinogenesis (Gong et al, 2015;Cheng et al, 2018), which is associated with changes in cell proliferation and invasion and in the cell cycle. This study is based on the hypothesis that MC-LR and ctHBx activate MAPK signaling to cause cancer by altering PP2A enzyme activity.…”

Potential Role and Clinical Value of PPP2CA in Hepatocellular Carcinoma

“…We performed a multivariate analysis, which showed that the PPP2CA gene may not be an independent risk factor for the poor prognosis of HCC. Gong et al 23 reported that PP2Ac expression plays a role in HCC tumorigenesis induced by HBV X protein, and PP2Ac protein overexpression is an independent predictor of poor OS of HCC patients. It can be seen that there are obvious differences between the two, which further proves the necessity of studying different subtypes of PP2Ac protein.…”