RESUMEN
Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM induced mtDNA perturbance. Clinical impacts of TFAM and mtDNA were further defined in carcinogen-induced mouse tongue cancer and clinical human HNC tissues; as the results showed that TFAM and mtDNA expression were significantly dropped in tumour compared with their normal counterparts and negatively correlated with disease progression. Collectively, our data uncovered a tumour-suppressing role of TFAM and mtDNA in determining HNC oncogenicity and potentially paved the way for development of TFAM/mtDNA based scheme for HNC diagnosis.
Asunto(s)
Carcinogénesis/genética , Proteínas de Unión al ADN/metabolismo , Genoma Mitocondrial , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Proteínas Mitocondriales/metabolismo , Oncogenes , Factores de Transcripción/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , ADN Mitocondrial/genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Glucosa/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Mitocondrias/metabolismo , Modelos Biológicos , Estrés Oxidativo , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ácido Pirúvico/metabolismo , Efecto Warburg en OncologíaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. It is well recognized that environmental challenges such as smoking, viral infection and alcohol consumption are key factors underlying HNSCC pathogenesis. Other than major clinical interventions (e.g., surgical resection, chemical and radiotherapy) that have been routinely practiced over years, adjuvant anticancer agents from Traditional Herbal Medicine (THM) are proposed, either alone or together with conventional therapies, to be experimentally effective for improving treatment efficacy in different cancers including HNSCCs. At a cellular and molecular basis, THM extracts could modulate different malignant indices via distinct signaling pathways and provide better control in HNSCC malignancy and its clinical complications such as radiotherapy-induced xerostomia/oral mucositis. In this article, we aim to systemically review the impacts of THM in regulating HNSCC tumorous identities and its potential perspective for clinical use.
