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

Highlights: • Human papillomavirus type 16 increases the levels of Met in infected keratinocytes. • EGFR upregulation by oncoprotein E5 is primarily responsible for Met upregulation, with E6 playing a minor role. • E5 increases the motility of HPV-containing keratinocytes. • Met activity is needed for proper viral gene expression and genome copy number maintenance. 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.