Regulation of the Wnt/β-Catenin Signaling Pathway by Human Papillomavirus E6 and E7 Oncoproteins

Abstract

Cell signaling pathways are the mechanisms by which cells transduce external stimuli, which control the transcription of genes, to regulate diverse biological effects. In cancer, distinct signaling pathways, such as the Wnt/β-catenin pathway, have been implicated in the deregulation of critical molecular processes that affect cell proliferation and differentiation. For example, changes in β-catenin localization have been identified in Human Papillomavirus (HPV)-related cancers as the lesion progresses. Specifically, β-catenin relocates from the membrane/cytoplasm to the nucleus, suggesting that this transcription regulator participates in cervical carcinogenesis. The E6 and E7 oncoproteins are responsible for the transforming activity of HPV, and some studies have implicated these viral oncoproteins in the regulation of the Wnt/β-catenin pathway. Nevertheless, new interactions of HPV oncoproteins with cellular proteins are emerging, and the study of the biological effects of such interactions will help to understand HPV-related carcinogenesis. This review addresses the accumulated evidence of the involvement of the HPV E6 and E7 oncoproteins in the activation of the Wnt/β-catenin pathway.

E6/E7-P53-POU2F1-CTHRC1 axis promotes cervical cancer metastasis and activates Wnt/PCP pathway

“…The E6 and E7 oncoproteins interfere with cell cycle regulators and induce genomic instability, which results in a malignant phenotype19. In addition to cervical cancer, E6/E7 is also associated with other tumors.…”

The levels of epithelial anchor proteins β-catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8

“…The role of the Wnt/b-catenin pathway in the development of different types of skin neoplasm has not been fully elucidated yet. Previous research described a relocalization of b-catenin from the plasma membrane to the nucleus in the presence of the E6/E7 oncoproteins of the high-risk a-HPV type 16 (Bello et al, 2015), which is associated with cervical and oropharyngeal cancer (Hübbers & Akgül, 2015). Our results demonstrated that the levels of membrane-tethered b-catenin are elevated in HPV8-E7 positive cutaneous keratinocytes.…”

Deregulation of the Notch pathway as a common road in viral carcinogenesis

“…29 Moreover, activating phosphorylations of NICD can be conducted by GSK3β which forms part of the Wnt degradation complex. 30 In contrast, Wnt can modulate Notch signaling activity through direct inhibition of RBP-Jĸ by the disheveled protein, which mediates β-catenin half-life. 31 The phosphatidylinositol-3-kinase (PI3K) pathway is a key regulator of cell survival; it transduces signals from growth factors and cytokines by generating phospholipids which activate Akt.…”

“…Wnt is known to affect the Notch signaling pathway by promoting JAG1 and NUMB expression . Moreover, activating phosphorylations of NICD can be conducted by GSK3β which forms part of the Wnt degradation complex . In contrast, Wnt can modulate Notch signaling activity through direct inhibition of RBP‐Jĸ by the disheveled protein, which mediates β‐catenin half‐life …”