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1.
Int J Mol Sci ; 23(3)2022 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-35162973

RESUMEN

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor prognosis. So far, the EGFR inhibitor cetuximab is the only approved targeted therapy. A deeper understanding of the molecular and genetic basis of HNSCC is needed to identify additional targets for rationally designed, personalized therapeutics. The transcription factor EVI1, the major product of the MECOM locus, is an oncoprotein with roles in both hematological and solid tumors. In HNSCC, high EVI1 expression was associated with an increased propensity to form lymph node metastases, but its effects in this tumor entity have not yet been determined experimentally. We therefore overexpressed or knocked down EVI1 in several HNSCC cell lines and determined the impact of these manipulations on parameters relevant to tumor growth and invasiveness, and on gene expression patterns. Our results revealed that EVI1 promoted the proliferation and migration of HNSCC cells. Furthermore, it augmented tumor spheroid formation and the ability of tumor spheroids to displace an endothelial cell layer. Finally, EVI1 altered the expression of numerous genes in HNSCC cells, which were enriched for Gene Ontology terms related to its cellular functions. In summary, EVI1 represents a novel oncogene in HNSCC that contributes to cellular proliferation and invasiveness.


Asunto(s)
Neoplasias de Cabeza y Cuello , Proteína del Locus del Complejo MDS1 y EV11 , Carcinoma de Células Escamosas de Cabeza y Cuello , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Humanos , Proteína del Locus del Complejo MDS1 y EV11/genética , Invasividad Neoplásica , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Factores de Transcripción/genética
2.
Oncol Res ; 32(1): 1-17, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38188682

RESUMEN

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers worldwide. The main risk factors are consumption of tobacco products and alcohol, as well as infection with human papilloma virus. Approved therapeutic options comprise surgery, radiation, chemotherapy, targeted therapy through epidermal growth factor receptor inhibition, and immunotherapy, but outcome has remained unsatisfactory due to recurrence rates of ~50% and the frequent occurrence of second primaries. The availability of the human genome sequence at the beginning of the millennium heralded the omics era, in which rapid technological progress has advanced our knowledge of the molecular biology of malignant diseases, including HNSCC, at an unprecedented pace. Initially, microarray-based methods, followed by approaches based on next-generation sequencing, were applied to study the genetics, epigenetics, and gene expression patterns of bulk tumors. More recently, the advent of single-cell RNA sequencing (scRNAseq) and spatial transcriptomics methods has facilitated the investigation of the heterogeneity between and within different cell populations in the tumor microenvironment (e.g., cancer cells, fibroblasts, immune cells, endothelial cells), led to the discovery of novel cell types, and advanced the discovery of cell-cell communication within tumors. This review provides an overview of scRNAseq, spatial transcriptomics, and the associated bioinformatics methods, and summarizes how their application has promoted our understanding of the emergence, composition, progression, and therapy responsiveness of, and intercellular signaling within, HNSCC.


Asunto(s)
Células Endoteliales , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/terapia , Perfilación de la Expresión Génica , Biología Computacional , Progresión de la Enfermedad , Análisis de Secuencia de ARN , Microambiente Tumoral/genética
3.
Leukemia ; 35(10): 2827-2839, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33782537

RESUMEN

Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/patología , Proteínas de Microfilamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Animales , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/genética , Proteínas de Neoplasias/genética , Pronóstico , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Tasa de Supervivencia
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