MEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors

Abstract

Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or “high-risk” HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.

Cobimetinib Sensitizes Cervical Cancer to Paclitaxel via Suppressing Paclitaxel-Induced ERK Activation

“…We further demonstrate that HPV-positive cells are more sensitive than HPVnegative cells to cobimetinib. This is consistent with the previous report that MEK/ERK signaling is a critical regulator of HPV oncogene expression and thus therapeutic targets for HPV-induced tumors [16]. Apart from efficacy studies of cobimetinib as single drug, our combination studies demonstrated that combination of cobimetinib and paclitaxel was synergistic in all tested cervical cancer cell lines (Fig.…”

“…Human papilloma virus (HPV) infection plays an essential role in cervical carcinogenesis and development [15]. MEK/ERK signaling is a critical regulator of HPV oncogene expression and MEK/ERK inhibition is thus a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression, and treat HPV neoplasia [16]. We thus speculate that inhibition of MEK/ERK by cobimetinib is likely to sensitize cervical cancer to chemotherapy.…”

Infectious Titres of Human Papillomaviruses (HPVs) in Patient Lesions, Methodological Considerations in Evaluating HPV Infectivity and Implications for the Efficacy of High-Level Disinfectants

“…[13,33], and detection is abrogated by antibody-mediated neutralisation of virions [12,34À36]. Therefore, HaCaT cells were inoculated with viral stocks and E1^E4 transcripts were quantified after 5 min (T = 0 h), 24 h, or 48 h. In parallel, virus stocks were incubated with genotype-specific neutralising antibodies prior to inoculation and infection for 48 h. Infection for 48 h allows maximal viral transcription without permitting cells to become overly confluent, which we show suppresses early HPV transcription [37]. Each QV stock and the xenograft HPV11 virus exposures were devoid of detectable E1^E4 transcripts at 0 h p.i., and as expected, HPV mRNA levels increased substantially after 48 h p.i.…”

Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5

“…Increased ERK phosphorylation was found in neural progenitor cells [ 50 ] and the rat fibroblast cell line 3Y1 [ 51 ], and human keratinocytes expressing HPV oncogene E7 or inhibitors of ERK signaling can reduce oncogene expression and inhibit a neoplastic phenotype through EGFR/MEK/ERK signaling [ 52 ] or K-Ras/ERK signaling [ 53 , 54 ]. In a skin carcinogenesis mouse model, papilloma formation was found in mice lacking DUSP5 and its regulation of nuclear ERK activity also served DUSP5 as tumor suppressor in epidermis Ras modulation [ 55 ].…”