RESUMEN
Our previous study reported that Epstein-Barr virus(EBV)-encoded latent membrane protein 1 (LMP1) could induce development of CD44(+/High) stem-like cells in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms that underlie modulation of cancer stem cells (CSCs) in NPC remain unclear. Here, we show that LMP1 induced CSC-like properties through promotion of the expression of epithelial-mesenchymal transition-like cellular markers and through alterations in differentiation markers. Furthermore, LMP1 activated and triggered phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which subsequently stimulated expression of CSC markers, development of side population and tumor sphere formation. This suggests that PI3K/AKT pathway has an important role in the induction and maintenance of CSC properties in NPC. Similarly, PI3K/AKT pathway was also activated by phosphorylase in LMP1-induced CD44(+/High) cells. In addition, LMP1 greatly increased expression of miR-21 and downregulated expression of the miR-21 target, PTEN. Overexpression of miR-21 by transfection of miR-21 mimics into LMP1-transformed cells led to phosphorylase-mediated activation of the PI3K/AKT pathway and induction of CSCs. On the contrary, phosphorylation of the PI3K/AKT pathway and the expression of CSC were reversed by an miR-21 inhibitor. The specific inhibitor (Ly294002) of PI3K/AKT pathway significantly decreased expression of miR-21 and CSC markers and upregulated the expression of PTEN, which indicates that miR-21 and PTEN are the downstream effectors of PI3K/AKT and that expression of these two effectors are related to the development of NPC CSCs. Taken together, our novel findings indicate that LMP1, PI3K/AKT, miR-21 and PTEN constitute a positive feedback loop and have a key role in LMP1-induced CSCs in NPC.
Asunto(s)
Neoplasias Nasofaríngeas/metabolismo , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de la Matriz Viral/metabolismo , Adulto , Anciano , Animales , Línea Celular , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Immunoblotting , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Trasplante Heterólogo , Proteínas de la Matriz Viral/genéticaRESUMEN
One thousand three hundred and two patients with carcinoma of the nasopharynx were initially treated with radiation therapy at this hospital in 1974. The overall 1-, 3-, 5-, and 10-year survival rates were 89.86%, 60.60%, 47%, and 33.03% respectively. At the end of the radiotherapeutic course the residual lesion rate was 10.52% in the nasopharynx 17.27% in cervical lymphnode. In about one-half of the cases with residual lesions, the masses disappeared without further treatment. Prognosis was not improved in the group with supplemental doses. The recurrence rates of the primary nasopharyngeal and metastatic cervical lesion were 18.43%, and 16.12% respectively within 10 years after initial treatment. The 10-year survival rate of the patients with a second course of radiotherapy was 15.04%, higher than of those not retreated (4.9%). Data of this group also reveal that the present pathological classification cannot reflect the degree of prognosis. Increase dosage or combination with chemotherapy did not improve the prognosis. Radiation encephalomyetic damage is discussed.