Interaction of viral oncogenic proteins with the Wnt signaling pathway

Abstract

It is estimated that up to 20% of all types of human cancers worldwide are attributed to viruses. The genome of oncogenic viruses carries genes that have protein products that act as oncoproteins in cell proliferation and transformation. The modulation of cell cycle control mechanisms, cellular regulatory and signaling pathways by oncogenic viruses, plays an important role in viral carcinogenesis. Different signaling pathways play a part in the carcinogenesis that occurs in a cell. Among these pathways, the Wnt signaling pathway plays a predominant role in carcinogenesis and is known as a central cellular pathway in the development of tumors. There are three Wnt signaling pathways that are well identified, including the canonical or Wnt/β-catenin dependent pathway, the noncanonical or β-catenin-independent planar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca2+ pathway. Most of the oncogenic viruses modulate the canonical Wnt signaling pathway. This review discusses the interaction between proteins of several human oncogenic viruses with the Wnt signaling pathway.

Keywords: Canonical pathway; Carcinogenesis; Oncogenic viruses; Wnt signaling; β-catenin.

Figure 1

The schematic representation for the possible interaction of viral oncogene proteins with various levels of Wnt/β-catenin cell signaling cascade. (HBV): (1) hypermethylation of E-cadherin, (2) SFRP1 and SFRP5 promoters via HBx protein; (3) dislocating of β-catenin from the destruction complex by binding to APC; (4) HBx-mediated suppression of GSK3β by src kinases, (5) overexpression of URG7 and the final inactivation of GSK3β. (HCV): (6) HCV core protein mediated-hypermethylation of E-cadherin promoter down-regulates E-cadherin expression and thereby β-catenin accumulation; (7) silencing of SFRP1expression by hypermethylation of its promoter; (8) upregulation of miR-155 gene and targeting of APC. (HIV): (9) Tat protein activates PI3K/AKT signaling pathway and inactivates GSK3β; (10) Nef protein compete for the similar site occupied by LEF/TCF on β-catenin. (HTLV-1): (11) Tax protein interacts with DAPLE (disheveled-associating protein) to trigger the canonical Wnt pathway; (12) Tax raise PI3K/Akt activity, resulting in the phosphorylation and inactivation of GSK3β. (EBV): (12) LMP2A activates PI3K/Akt pathway, resulting in the phosphorylation and inactivation of GSK3β. (13) LMP1 inhibits Siah1 (an E3 ubiquitin ligase), which is involved in ubiquitination and proteasomal degradation of β-catenin; (HPV): (13) E6 oncoprotein inhibits Siah1, which is involved in ubiquitination and proteasomal degradation of β-catenin; (14) E6 binds to Dsh and disrupts the destruction complex (β-catenin stabilization). (HHV-8): (12) LANA protein promotes PI3K/Akt activity, resulting in the phosphorylation and inactivation of GSK3β