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1.
Br J Cancer ; 125(4): 547-560, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34079080

RESUMO

BACKGROUND: Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis. METHODS: Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays. RESULTS: Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients. CONCLUSION: We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Ubiquitina Tiolesterase/metabolismo , Regulação para Cima , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico , Estabilidade Proteica , Análise de Sobrevida , Ubiquitina Tiolesterase/genética , Ubiquitinação
2.
Cell Death Dis ; 9(12): 1142, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442925

RESUMO

Radiation-induced bystander effect (RIBE) is a poorly understood phenomenon wherein non-targeted cells exhibit effects of radiation. We have reported that cell-free chromatin (cfCh) particles that are released from dying cells can integrate into genomes of surrounding healthy cells to induce DNA damage and inflammation. This raised the possibility that RIBE might be induced by cfCh released from irradiated dying cells. When conditioned media from BrdU-labeled irradiated cells were passed through filters of pore size 0.22 µm and incubated with unexposed cells, BrdU-labeled cfCh particles could be seen to readily enter their nuclei to activate H2AX, active Caspase-3, NFκB, and IL-6. A direct relationship was observed with respect to activation of RIBE biomarkers and radiation dose in the range of 0.1-0 Gy. We confirmed by FISH and cytogenetic analysis that cfCh had stably integrated into chromosomes of bystander cells and had led to extensive chromosomal instability. The above RIBE effects could be abrogated when conditioned media were pre-treated with agents that inactivate cfCh, namely, anti-histone antibody complexed nanoparticles (CNPs), DNase I and a novel DNA degrading agent Resveratrol-copper (R-Cu). Lower hemi-body irradiation with γ-rays (0.1-50 Gy) led to activation of H2AX, active Caspase-3, NFκB, and IL-6 in brain cells in a dose-dependent manner. Activation of these RIBE biomarkers could be abrogated by concurrent treatment with CNPs, DNase I and R-Cu indicating that activation of RIBE was not due to radiation scatter to the brain. RIBE activation was seen even when mini-beam radiation was delivered to the umbilical region of mice wherein radiation scatter to brain was negligible and could be abrogated by cfCh inactivating agents. These results indicate that cfCh released from radiation-induced dying cells are activators of RIBE and that it can be prevented by treatment with appropriate cfCh inactivating agents.


Assuntos
Cromatina/genética , Inflamação/tratamento farmacológico , Lesões por Radiação/tratamento farmacológico , Resveratrol/farmacologia , Animais , Efeito Espectador/efeitos dos fármacos , Efeito Espectador/efeitos da radiação , Caspase 3/genética , Sistema Livre de Células/efeitos dos fármacos , Sistema Livre de Células/efeitos da radiação , Cromatina/efeitos dos fármacos , Cromatina/efeitos da radiação , Cobre/farmacologia , Meios de Cultivo Condicionados/farmacologia , Dano ao DNA/efeitos da radiação , Desoxirribonuclease I/genética , Modelos Animais de Doenças , Raios gama/efeitos adversos , Histonas/genética , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-6/genética , Camundongos , NF-kappa B/genética , Lesões por Radiação/genética , Lesões por Radiação/patologia
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