MmuPV1 E7 promotes phenotypes associated with "high-risk" HPV infection in mouse keratinocytes

The E7 oncoprotein of mouse papillomavirus (MmuPV1) plays a pivotal role in both viral infection and cancer development. While earlier studies have identified key cellular targets of MmuPV1 E7, such as pRB and PTPN14, the broader impact of MmuPV1 E7 on keratinocyte homeostasis and shared activities with human papillomavirus (HPV) E7 remains unclear. In this study, we employed proteomic and transcriptomic analyses using our established mouse keratinocyte model-previously instrumental in uncovering a novel function of MmuPV1 E6-to investigate the biological consequences of MmuPV1 E7 expression in mouse keratinocytes. Our findings reveal that MmuPV1 E7 induces cellular changes reminiscent of those driven by "high-risk" HPV infection implicated in cervical cancer. Notably, MmuPV1 E7 did not activate canonical E2F-responsive gene expression or promote proliferation, reinforcing the idea that MmuPV1 E6 is the primary driver of cell cycle activation. However, MmuPV1 E7 expression led to a significant accumulation of stress keratin 17, a marker associated with immune evasion and elevated in both HPV16 transgenic models and MmuPV1 infections. Additionally, we observed enhanced PI3K-AKT-mTOR signaling, with increased levels of phosphorylated S6 kinase and heightened sensitivity to epidermal growth factor stimulation. Collectively, these results underscore the role of MmuPV1 E7 in promoting oncogenic phenotypes and highlight its relevance as a model for studying the molecular underpinnings of "high-risk" HPV-driven disease.

In this study, we determined the ability of the MmuPV1 E7 oncoprotein in promoting disruption of keratinocyte homeostasis in mouse keratinocytes. Using a multiomics approach, we observed that MmuPV1 E7 promoted several phenotypes associated with "high-risk" human papillomavirus (HPV) infection. Specifically, we confirmed that MmuPV1 E7 does not increase E2F-responsive gene expression and proliferation of mouse keratinocytes. We did find that MmuPV1 E7 was able to increase the expression of stress keratin 17, which promotes immune evasion in papillomavirus infections. Finally, MmuPV1 E7 showed increased expression of genes associated with PI3K-AKT-mTOR signaling. Consistent with this observation, MmuPV1 E7-expressing mouse keratinocytes had elevated phosphorylation of S6 kinase. We also found that MmuPV1 E7 potentiates this signaling through increased sensitivity to epidermal growth factor stimulation. Our collective data show that MmuPV1 E7 promotes several phenotypes associated with "high-risk" HPV infection and cancers.