RESUMEN
Cervical cancer (CC) is usually initiated by infection with high-risk types of human papillomavirus (HPV). The HPV E6 and E7 proteins target p53 and RB, respectively, but other cellular targets likely exist. We generated uterus-specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Mutant cervical epithelial cells showed YAP1-dependent hyperproliferation, altered self-renewal, impaired contact inhibition, and chromosomal instability. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion. In human CC, strong YAP1 activation was observed from the precancerous stage. Human cells overexpressing HPV16 E6/E7 showed inactivation of not only p53 and RB but also PTPN14, boosting YAP1 activation. Estrogen, cigarette smoke condensate, and PI3K hyperactivation all increased YAP1 activity in human cervical epithelial cells, and PTPN14 depletion along with PI3K activation or estrogen treatment further enhanced YAP1. Thus, immediate CC onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo-YAP1 signaling a major CC driver.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma/metabolismo , Proteínas de Ciclo Celular/metabolismo , Caries Radicular/metabolismo , Animales , Carcinoma/virología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Línea Celular , Línea Celular Tumoral , Células Epiteliales/metabolismo , Células Epiteliales/virología , Estrógenos/metabolismo , Humanos , Ratones , Ratones Noqueados , Proteínas Oncogénicas Virales/metabolismo , Papillomaviridae/metabolismo , Papillomaviridae/patogenicidad , Proteínas E7 de Papillomavirus/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Represoras/metabolismo , Caries Radicular/virología , Transducción de Señal/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Señalizadoras YAPRESUMEN
Regulatory T-cells induced via IL-2 and TGFß in vitro (iTreg) suppress immune cells and are potential therapeutics during autoimmunity. However, several reports described their re-differentiation into pathogenic cells in vivo and loss of their key functional transcription factor (TF) FOXP3 after T-cell antigen receptor (TCR)-signalling in vitro. Here, we show that TCR-activation antagonizes two necessary TFs for foxp3 gene transcription, which are themselves regulated by phosphorylation. Although the tyrosine phosphatase PTPN2 is induced to restrain IL-2-mediated phosphorylation of the TF STAT5, expression of the TF FOXO1 is downregulated and miR-182, a suppressor of FOXO1 expression, is upregulated. TGFß counteracts the FOXP3-depleting TCR-signal by reassuring FOXO1 expression and by re-licensing STAT5 phosphorylation. Overexpressed phosphorylation-independent active versions of FOXO1 and STAT5 or knockdown of PTPN2 restores FOXP3 expression despite TCR-signal and absence of TGFß. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation.