PPP2R5A has been reported to be involved in the regulation of signaling pathways of tumorigenesis . Studies have shown that PP2A negatively regulated the cell anti-apoptotic factor Bcl2, PPP2R5A assisted PP2A in its functions and promoted the occurrence of apoptosis [11, 25]. Yamamoto et al. reported that PPP2R5A helped PP2A locate the important proto-oncoprotein β-Catenin in the WNT pathway by binding to the scaffold protein Axin, and promoted β-Catenin degradation . Rodriguez et al. found that the lack of function of the PPP2R5A protein family led to the hyperfunction of the protein kinase B (AKT) family and promoted the activation of the WNT pathway and the occurrence of tumors [12, 26]. In addition, studies have shown that after inhibited the expression of PPP2R5A by microRNA-218, the WNT pathway would be significantly activated . PPP2R5A can also assist PP2A to localize to c-Myc protein and promote the dephosphorylation and degradation of c-Myc protein . These oncoproteins play an important role in the unlimited proliferation, infiltration and metastasis of tumor cells, and cell death resistance.
It is worth noting that some studies have found that viral infection could affect the expression of PPP2R5A. After treated cells with ceramide or double-stranded RNA, eukaryotic translation initiation factor 2 alpha kinase 2 (PKR) itself activated and phosphorylated the 28th serine of PPP2R5A, which enhanced the inhibitory effect of PP2A on protein synthesis and induction of apoptosis, thereby inhibiting viral infection [28, 29]. However, hepatitis C virus (HCV) mRNA can promote Staufen1 to competitively inhibit the binding of viral mRNA and PKR, and block the autophosphorylation activation of PKR , which can lead to the decline of PPP2R5A expression and function. The Vif protein produced by lentiviral infection can recruit Cullin-5 (CUL5) E3 ubiquitin ligase to induce the ubiquitination and degradation of PPP2R5A [19, 31]. These examples demonstrated the antagonism of PPP2R5A and viral infection in the co-evolution of virus-host. However, the effect of HBV infection on PPP2R5A has not been reported yet.
Based on the above results, the molecular mechanism of PPP22R5A in the occurrence and development of HCC is speculated as follows (Fig. 6): PPP2R5A exerts a tumor suppressor efficacy in hepatocytes. Under HBV-uninfected circumstances, when hepatocytes become cancerous, as one of the protective mechanisms, cells will up-regulate the expression of PPP2R5A. The high expression of PPP2R5A can inhibit the proliferation and metastasis of HCC cells. Therefore, the results of survival analysis showed that the higher the expression of PPP2R5A, the higher the PFS of HCC patients. But HBV is precisely the "nemesis" of PPP2R5A. When HCC patients are infected with HBV, HBV can down-regulate the content of PPP2R5A in cells, leading to a weakening of cellular self-protection mechanism. At this time, the expression of p-RAF, p-ERK, and p-AKT is up-regulated, and the activation of MAPK and AKT signaling pathways leads to an increase of β-Catenin, the key molecule of WNT signaling pathway, and an activation of WNT signaling pathway. The continuous activation of MAPK/AKT/WNT signaling pathways can promote cell proliferation and metastasis, thereby promoting the occurrence and development of HCC.
Combined with the fact that 85%-90% of HCC in China is closely related to HBV infection, it may be that HBV infection weakens the self-protection function of hepatocytes and increases the possibility of cell canceration.