E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(2), P. e1012914 - e1012914

Published: Feb. 7, 2025

Oncogenic types of human papillomaviruses (HPVs) are major carcinogens. The formation a trimeric complex between the HPV E6 oncoprotein, cellular ubiquitin ligase E6AP and p53 tumor suppressor protein leads to proteolytic degradation plays central role for HPV-induced cell transformation. We here uncover that silencing in HPV-positive cancer cells ultimately efficient induction senescence, revealing acts as potent anti-senescent factor these cells. Thus, although downregulation either or expression also partially pro-apoptotic, surviving repression proliferate further, whereas they become irreversibly growth-arrested upon repression. moreover show senescence following is mechanistically highly dependent on p53/p21 axis, other than known pro-senescent response combined viral E7 oncoproteins. Of further note, allows presence protein. Yet, despite mechanistic differences, pathways underlying effects E6/E7 converge by being both pocket proteins pRb p130. Taken together, our results hitherto unrecognized function cells, which essential their sustained proliferation. Our indicate interfering with could result therapeutically desired efficiently inducing an irreversible growth arrest. Since critical E6/E6AP/p53 transformation conserved different oncogenic types, this approach provide therapeutic strategy, not type-specific.

Language: Английский

Current and Emerging Insights into the Causes, Immunopathogenesis, and Treatment of Cutaneous Squamous Cell Carcinoma

Cancers, Journal Year: 2025, Volume and Issue: 17(10), P. 1702 - 1702

Published: May 19, 2025

The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks metastasis and recurrence, underscores importance identifying novel therapies validated biomarkers to augment patient management, particularly in context well-established advanced disease. Following a brief overview well-recognized epidemiology, clinical features, diagnosis cSCC, current review is focused on risk factors, most prominently excessive exposure ultraviolet radiation (UVR) as cause persistent, pro-tumorigenic mutagenesis, immune suppression. next phase encompasses an evaluation search for key driver mutations pathogenesis including role these other formation immunologically reactive neoepitopes. With respect additional mechanisms tumorigenesis, evasion prioritized, specifically involvement cell-free infiltrating cellular mediators Prominent amongst former are cytokine, transforming growth factor-β1 (TGF-β1), prostanoid, prostaglandin E2, emerging suppressive nucleoside adenosine. In case latter, tumor-infiltrating circulating regulatory T cells have been implicated being players. final sections update immunotherapy established disease, well novel, reliable lesional systemic potential guide management.

Language: Английский