Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells

Abstract

A subset of oral carcinomas is etiologically related to high-risk human papillomavirus (HR-HPV) infection, with HPV16 being the most frequent HR-HPV type found in these carcinomas. The oncogenic role of HR-HPV is strongly dependent on the overexpression of E6 and E7 oncoproteins, which, in turn, induce p53 and pRb degradation, respectively. Additionally, it has been suggested that HR-HPV oncoproteins are involved in the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducing cancer progression and metastasis. Previously, we reported that HPV16 E7 oncoprotein promotes Pirin upregulation resulting in increased epithelial–mesenchymal transition (EMT) and cell migration, with Pirin being an oxidative stress sensor and activator of NF-κB. In this study, we demonstrate the mechanism by which HPV16 E7-mediated Pirin overexpression occurs by promoting EGFR/PI3K/AKT1/NRF2 signaling, thus causing PIR/NF-κB activation in oral tumor cells. Our results demonstrate a new mechanism by which E7 contributes to oral cancer progression, proposing PIR as a potential new therapeutic target.

Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

“…Furthermore, both epidermal growth factor receptor/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (EGFR/MEK/ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways may be involved in the activation of Pirin by HPV-E7 oncoprotein in oral cells [63], which is in line with a previous report on transformed rat fibroblasts [93]. More recently, we demonstrated that EGFR/PI3K/AKT1/NRF2 signaling promotes Pirindependent canonical NF-κB activation, which, in turn, promotes oral cell migration [37]. Altogether, this strongly suggests a novel carcinogenic mechanism by which Pirin is involved in oral cancer, although the clinical consequences remain to be determined.…”

“…ABL2 is a cytoplasmic tyrosine kinase which coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics. Taken together, the functional association of Pirin with proteins involved in cytoskeleton reorganization partially explains the link between Pirin overexpression and increased cell migration in some cellular models [37,38]. Further experimental settings are warranted to elucidate the molecular mechanisms involved in these functional associations.…”

“…Upregulation of c-Rel and p65 through an interplay with Pirin, promotes cell migration and EMT [37] Abbreviations: TS: tobacco smoke; NF-κB: nuclear factor kappa B; NRF2: nuclear factor erythroid 2-related factor 2; BCL-3: B-cell lymphoma 3-encoded protein; EMT: epithelial-mesenchymal transition; HPV: human papillomavirus; Slug: zinc finger protein; ZEB: zinc finger E-box-binding homeobox protein; EGFR: epidermal growth factor receptor; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B. (1) HPV integrates into the host genome, overexpressing viral oncogenes (i.e., E7).…”

High-Risk Human Papillomavirus and Tobacco Smoke Interactions in Epithelial Carcinogenesis

“…Likewise, it was observed that PIR is upregulated by HR-HPV E7 oncoprotein dependent on EGFR/MEK/ERK and PI3K/Akt signaling pathways. Subsequently, Pirin protein induces NF-κB activation and is involved in EMT and migration in HPV-positive cervical cancer cells [158]. Taken together, these data indicate that PIR may be important in both TS and HPV-mediated carcinogenesis.…”

Spectrum and Incidence Trends of AIDS- and Non–AIDS-Defining Cancers between 2010 and 2015 in the French Dat'AIDS Cohort

“…It is worthy of note however that HPV infection and tobacco smoking interacted with each other, tobacco exposure enhancing HPV16-E6 and -E7 oncogene transcription (36) and overexpression of HPV 16-E7 oncoprotein contributing to oral cancer progression (37). These interactions could be modulated according to time of oral HPV infection and life course smoking trajectories which could modify the HNC risk (38).…”