Insufficient PINX1 expression stimulates telomerase activation by direct inhibition of EBV LMP1-NF-κB axis during nasopharyngeal carcinoma development.
Biochem Biophys Res Commun
; 514(1): 127-133, 2019 06 18.
Article
en En
| MEDLINE
| ID: mdl-31027734
ABSTRACT
OBJECTIVE:
Early malignant transformation of nasopharyngeal carcinoma(NPC) is associated with Epstein-Barr virus(EBV) infection and telomerase activation. The EBV latent membrane protein 1(LMP1) regulates expression of various genes by triggering NF-κB signaling pathway. PINX1 is a well-identified tumor suppressor gene by inhibiting telomerase activity and cancer cell growth. However, whether and how EBV inhibit PINX1 expression and activate telomerase in NPC is still incompletely elucidated.METHODS:
Immunohistochemistry, real-time PCR and Western blotting were utilized to explore the expression of PINX1. Chromatin immunoprecipitation(ChIP) and Dual-luciferase reporter assay were used to elucidate the regulatory mechanism between NF-κB and PINX1. TRAP-SYBR Green assay and Southern blotting were utilized to detect telomerase activity and telomere length. CCK8 and EdU tests were conducted to measure proliferation ability.RESULTS:
We demonstrated that PINX1 is down-regulated in NPC for the first time. Mechanistically, we found that LMP1 could inhibit the transcriptional activity of PINX1 by promoting the binding of p65 to three specific sites in PINX1 promoter, significantly, two(-1698/-1689, tgcaatttcc; -206/-197, cgggctttac) of which have not been reported. In addition, we also observed that LMP1 overexpression resulted in increased telomerase activity, prolonged telomere length and enhanced proliferation.CONCLUSION:
We first discovered EBV led to reduced PINX1 expression through LMP1-NF-κB-PINX1 axis, which up-regulated telomerase activity in NPC. And hence, the tumor cells acquired the ability to proliferate more exuberantly. This signaling pathway illustrates the relationship between EBV latent infection and telomerase activation, and further provides new thinking for early diagnosis and treatment in NPC.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de la Matriz Viral
/
Neoplasias Nasofaríngeas
/
FN-kappa B
/
Proteínas de Ciclo Celular
/
Telomerasa
/
Infecciones por Virus de Epstein-Barr
/
Proteínas Supresoras de Tumor
/
Carcinoma Nasofaríngeo
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2019
Tipo del documento:
Article
País de afiliación:
China