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1.
BMC Cancer ; 20(1): 597, 2020 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-32586280

RESUMEN

BACKGROUND: A major cause of disease-related death in nasopharyngeal carcinoma (NPC) is the development of distant metastasis (DM) despite combination chemoradiotherapy treatment. We previously identified and validated a four microRNA (miRNA) signature that is prognostic for DM. In this study, characterization of a key component of this signature, miR-34c, revealed its role in chemotherapy resistance. METHODS: Two hundred forty-six NPC patient biopsy samples were subject to comprehensive miRNA profiling and immunohistochemistry (IHC). Two human normal nasopharyngeal cell lines (immortalized; NP69 and NP460), as well as the NPC cell line C666-1, were used for miR-34c gain-of-function and loss-of-function experiments. Signaling pathways were assessed using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability was measured using the ATPlite assay. RESULTS: MiR-34c was downregulated in NPC patient samples, and confirmed in vitro to directly target SOX4, a master regulator of epithelial-to-mesenchymal transition (EMT). MiR-34c downregulation triggered EMT-representative changes in NP69 and NP460 whereby Snail, ZEB1, CDH2, and SOX2 were upregulated, while Claudin-1 and CDH1 were downregulated. Phenotypically, inhibition of miR-34c led to cisplatin resistance, whereas miR-34c over-expression sensitized NPC cells to cisplatin. TGFß1 decreased miR-34c and increased SOX4 expression in vitro. The TGFß receptor 1 inhibitor SB431542 reduced SOX4 expression and increased cisplatin sensitivity. Finally, IHC revealed that lower SOX4 expression was associated with improved overall survival in chemotherapy-treated NPC patients. CONCLUSION: miR-34c is downregulated in NPC. Repression of miR-34c was shown to increase SOX4 expression, which leads to cisplatin resistance, while TGFß1 was found to repress miR-34c expression. Taken together, our study demonstrates that inhibition of the TGFß1 pathway could be a strategy to restore cisplatin sensitivity in NPC.


Asunto(s)
Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , MicroARNs/metabolismo , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Factores de Transcripción SOXC/genética , Factor de Crecimiento Transformador beta1/metabolismo , Benzamidas/farmacología , Biopsia , Línea Celular Tumoral , Cisplatino/uso terapéutico , Dioxoles/farmacología , Regulación hacia Abajo , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Nasofaringe/patología , RNA-Seq , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores
2.
Lab Invest ; 95(8): 937-50, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26006018

RESUMEN

Epstein-Barr virus (EBV) infection is closely associated with several human malignancies including nasopharyngeal carcinoma (NPC). The EBV immediate-early protein BZLF1 is the key mediator that switches EBV infection from latent to lytic forms. The lytic form of EBV infection has been implicated in human carcinogenesis but its molecular mechanisms remain unclear. BZLF1 has been shown to be a binding partner of several DNA damage response (DDR) proteins. Its functions in host DDR remain unknown. Thus, we explore the effects of BZLF1 on cellular response to DNA damage in NPC cells. We found that expression of BZLF1 impaired the binding between RNF8 and MDC1 (mediator of DNA damage checkpoint 1), which in turn interfered with the localization of RNF8 and 53BP1 to the DNA damage sites. The RNF8-53BP1 pathway is important for repair of DNA double-strand breaks and DNA damage-induced G2/M checkpoint activation. Our results showed that, by impairing DNA damage repair as well as abrogating G2/M checkpoint, BZLF1 induced genomic instability and rendered cells more sensitive to ionizing radiation. Moreover, the blockage of 53BP1 and RNF8 foci formation was recapitulated in EBV-infected cells. Taken together, our study raises the possibility that, by causing mis-localization of important DDR proteins, BZLF1 may function as a link between lytic EBV infection and impaired DNA damage repair, thus contributing to the carcinogenesis of EBV-associated human epithelial malignancies.


Asunto(s)
Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transactivadores/metabolismo , Transactivadores/farmacología , Proteínas Adaptadoras Transductoras de Señales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Roturas del ADN de Doble Cadena , Daño del ADN/fisiología , Reparación del ADN/fisiología , Células HeLa , Herpesvirus Humano 4 , Interacciones Huésped-Patógeno , Humanos , Neoplasias Nasofaríngeas , Proteínas Nucleares/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53 , Ubiquitina-Proteína Ligasas
3.
Cancer Res ; 62(6): 1662-8, 2002 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11912137

RESUMEN

Chromosome instability is a commonly observed feature in ovarian carcinoma. Mitotic checkpoint controls are thought to be essential for accurate chromosomal segregation, and MAD2 is a key component of this checkpoint. In this study, we investigated the competence of the mitotic checkpoint and its relationship to the expression of MAD2 protein in seven ovarian cancer cell lines. We found that a significant number (43%, three of seven cell lines) of the tested ovarian cancer cells failed to arrest in the G(2)-M phase of the cell cycle in response to microtubule disruption. This loss of mitotic checkpoint control was associated with reduced expression of the MAD2 protein. To additionally understand the significance of the MAD2 to mitotic checkpoint control, we established an inducible expression system in which MAD2 was induced by the addition of ponasterone A. Notably, the induced expression of MAD2 in two checkpoint-defective ovarian cancer cell lines led to the restoration of mitotic checkpoint response to spindle-disrupting agents. Taken together, our findings suggest that the steady-state amount of MAD2 inside cells may represent a molecular switch for mitotic checkpoint control. This provides a novel insight into the molecular basis of CIN in ovarian carcinoma and has implications for effective use of checkpoint-targeting drugs.


Asunto(s)
Proteínas de Unión al Calcio/biosíntesis , Mitosis/fisiología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas de Unión al Calcio/genética , Ciclo Celular/fisiología , Proteínas de Ciclo Celular , Femenino , Humanos , Proteínas Mad2 , Neoplasias Ováricas/genética , Plásmidos/genética , Proteínas Represoras , Transfección , Células Tumorales Cultivadas
4.
Cancer Lett ; 343(1): 24-32, 2014 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-24041865

RESUMEN

The dual PI3K-mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro, induce G1 cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo. A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo. The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Imidazoles/farmacología , Neoplasias Nasofaríngeas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Quinolinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Antineoplásicos/farmacología , Carcinoma , Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular , Cisplatino/farmacología , Activación Enzimática , Femenino , Humanos , Concentración 50 Inhibidora , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Desnudos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Trasplante de Neoplasias , Paclitaxel/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
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