Human papillomavirus type 16 E5-mediated upregulation of Met in human keratinocytes

Abstract

Human papillomaviruses (HPVs) cause benign lesions that can lead to malignancy. How cellular changes induced by viral oncogenes contribute to the progeny virion production is not always clear. Stromally-derived growth factors and their receptors are critical for development of malignancy, but their impact on the pre-malignant HPV life cycle is unknown. We show that HPV16 increases levels of Met, a growth factor receptor critical for tumor cell invasion, motility, and cancer metastasis. The viral oncogene E5 is primarily responsible for Met upregulation, with E6 playing a minor role. Met induction by E5 requires the epidermal growth factor receptor, which is also increased by E5 at the mRNA level. E5-induced Met contributes motility of HPV-containing cells. Finally, Met signaling is necessary for viral gene expression, particularly in the differentiation-dependent phase of the viral life cycle. These studies show a new role for E5 in epithelial-stromal interactions, with implications for cancer development.

Suppression of Stromal Interferon Signaling by Human Papillomavirus 16

“…E6 and E7 are both known to interfere with the IFN response, and both have been shown to regulate the expression of soluble factors that are capable of acting on the stroma (39,48,81). Because E6 and E7 are both expressed at normal levels in E5 Stop cells (34), the suppressive effects of these two oncogenes would still be present. This explains the observation that E5 Stop cells retained a portion of wild-type HPV16's ability to suppress stromal innate immune responses.…”

“…Loss of E6 or E7 from the viral genome prevents episomal replication and immortalization (70), making it difficult to examine the roles of these genes in the context of the viral genome in our experimental system. However, the oncogene E5 is known to regulate responses of the infected cell to its environment (23), and HPV16 harboring a stop codon mutation in the E5 open reading frame could be (34). These cells maintain the HPV16 genome at levels equivalent to the wild type and have normal levels of E6 and E7 expression (34).…”

“…However, the oncogene E5 is known to regulate responses of the infected cell to its environment (23), and HPV16 harboring a stop codon mutation in the E5 open reading frame could be (34). These cells maintain the HPV16 genome at levels equivalent to the wild type and have normal levels of E6 and E7 expression (34). They are therefore a valuable tool to understand the role of E5 in the context of the episomal genome.…”

“…Next, group 2 includes genes that were suppressed approximately equally in the presence or absence of E5. These genes were presumably suppressed by the actions of E6 and/or E7 (which are expressed at normal levels in E5 Stop cells [34]) with no contribution from E5. Group 3 includes genes whose expression levels were partially restored, indicating that E5 contributed to suppression but is not responsible for the whole effect.…”

“…The best understood activity of E5 is to enhance signaling from the epidermal growth factor receptor (EGFR) (28,29). E5 interacts with or regulates several growth factor systems, including transforming growth factor beta (TGF-␤), hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) (30)(31)(32)(33)(34). Other functions have been reported, including inhibition of MHC-I expression (23).…”