RESUMO
Proteins of the lysyl oxidase (LOX) family are important modulators of the extracellular matrix. However, they have an important role in the tumour development as well as in tumour progression. To evaluate the diagnostic and prognostic value of the LOX protein in oral and oropharyngeal squamous cell carcinoma (OSCC) we performed QRT-PCR and immunohistochemical analysis on two tissue microarrays (622 tissue samples in total). Significantly higher LOX expression was detected in high grade dysplastic oral mucosa as well as in OSCC when compared to normal oral mucosa (P < 0.001). High LOX expression was correlated with clinical TNM stage (P = 0.020), lymph node metastases for the entire cohort (P < 0.001), as well as in the subgroup of small primary tumours (T1/T2, P < 0.001). Moreover, high LOX expression was correlated with poor overall survival (P = 0.004) and disease specific survival (P = 0.037). In a multivariate analysis, high LOX expression was an independent prognostic factor, predicting unfavourable overall survival. In summary, LOX expression is an independent prognostic biomarker and a predictor of lymph node metastasis in OSCC. Moreover, LOX overexpression may be an early phenomenon in the pathogenesis of OSCC and thus an attractive novel target for chemopreventive and therapeutic strategies.
Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/genética , Neoplasias Orofaríngeas/genética , Prognóstico , Proteína-Lisina 6-Oxidase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Neoplasias Bucais/secundário , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/secundário , Valor Preditivo dos Testes , Análise de Sobrevida , SobreviventesRESUMO
Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent for primary effusion lymphoma (PEL), a non-Hodgkin type lymphoma manifesting as an effusion malignancy in the affected individual. Although KSHV has been recognized as a tumor virus for over a decade, the pathways for its tumorigenic conversion are incompletely understood, which has greatly hampered the development of efficient therapies for KSHV-induced malignancies like PEL and Kaposi's sarcoma. There are no current therapies effective against the aggressive, KSHV-induced PEL. Here we demonstrate that activation of the p53 pathway using murine double minute 2 (MDM2) inhibitor Nutlin-3a conveyed specific and highly potent activation of PEL cell killing. Our results demonstrated that the KSHV latency-associated nuclear antigen (LANA) bound to both p53 and MDM2 and that the MDM2 inhibitor Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. Together with our results indicating that KSHV-infection activated DNA damage signaling, these findings contribute to the specificity of the cytotoxic effects of Nutlin-3a in KSHV-infected cells. Moreover, we showed that Nutlin-3a had striking antitumor activity in vivo in a mouse xenograft model. Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.
Assuntos
Regulação Neoplásica da Expressão Gênica , Genes p53 , Herpesvirus Humano 8/fisiologia , Linfoma/virologia , Sarcoma de Kaposi/genética , Proteína Supressora de Tumor p53/genética , Animais , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 4/fisiologia , Herpesvirus Humano 8/patogenicidade , Humanos , Imidazóis/farmacologia , Linfoma/genética , Camundongos , Piperazinas/farmacologia , Sarcoma de Kaposi/virologia , Transplante Heterólogo , Latência ViralRESUMO
Several transcription factors have been implicated as playing a role in myelopoiesis. PU.1, an ets-family transcription factor, is required for the development of myeloid and lymphoid lineages, whereas the transcription factor CCAAT-enhancer binding protein family member C/EBPalpha is essential for granulocyte development. We present here the first evidence that C/EBPalpha blocks the function of PU.1. PU.1 and C/EBPalpha interact physically and colocalize in myeloid cells. As a consequence of this interaction, C/EBPalpha can inhibit the function of PU.1 to activate a minimal promoter containing only PU.1 DNA-binding sites. We further demonstrate that the leucine zipper in the DNA-binding domain of C/EBPalpha interacts with the beta3/beta4 region in the DNA-binding domain of PU.1 and as a result displaces the PU.1 coactivator c-Jun. Finally, C/EBPalpha blocks PU.1-induced dendritic cell development from CD34+ human cord blood cells. The functional blocking of PU.1 by C/EBPalpha could be the mechanism by which C/EBPalpha inhibits cell fates specified by PU.1 and directs cell development to the granulocyte lineage.
