RESUMO
Lung mucoepidermoid carcinoma (MEC) is a very poorly characterized rare subtype of non-small-cell lung cancer (NSCLC) associated with more favorable prognoses than other forms of intrathoracic malignancies. We have previously identified that heme oxygenase-1 (HO-1, encoded by HMOX1) inhibits MEC tumor growth and modulates the transcriptome of microRNAs. Here we investigate the role of a major upstream regulator of HO-1 and a master regulator of cellular antioxidant responses, transcription factor Nrf2, in MEC biology. Nrf2 overexpression in the NCI-H292 MEC cell line mimicked the phenotype of HO-1 overexpressing cells, leading to inhibition of cell proliferation and migration and down-regulation of oncogenic miR-378. HMOX1 silencing identified HO-1 as a major mediator of Nrf2 action. Nrf2- and HO-1 overexpressing cells exhibited strongly diminished expression of multiple matrix metalloproteinases and inflammatory cytokine interleukin-1ß, which was confirmed in an NCI-HO-1 xenograft model. Overexpression of HO-1 altered not only human MMP levels in tumor cells but also murine MMP levels within tumor microenvironment and metastatic niche. This could possibly contribute to decreased metastasis to the lungs and inhibitory effects of HO-1 on MEC tumor growth. Our profound transcriptome analysis and molecular characterization of the mucoepidermoid lung carcinoma helps to understand the specific clinical presentations of these tumors, emphasizing a unique antitumoral role of the Nrf2-HO-1 axis.
Assuntos
Carcinoma Mucoepidermoide/prevenção & controle , Regulação Neoplásica da Expressão Gênica , Heme Oxigenase-1/metabolismo , Neoplasias Pulmonares/prevenção & controle , Metaloproteinases da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Apoptose , Western Blotting , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Proliferação de Células , Regulação para Baixo , Imunofluorescência , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS AND BACKGROUND: Bronchial mucoepidermoid carcinoma is a rare disease in children, and lobectomy is traditionally considered as a first-line treatment. As the tumor is characterized by intraluminal growth, low malignancy and superficial infiltration of bronchial walls, bronchoscopic interventional therapy may provide an alternative treatment with favorable results. The aim of the study was to evaluate the efficacy and safety of bronchoscopic therapies for bronchial mucoepidermoid carcinoma in children. METHODS AND STUDY DESIGN: Clinical manifestations, multiple bronchoscopic interventions and outcomes in 6 children with bronchial mucoepidermoid carcinoma were retrospectively analyzed. RESULTS: The median age was 8.7 years (range 4 to 12 years). All the tumors were located in the lobar bronchus and were detected by computerized tomography. Diagnoses of low-grade mucoepidermoid carcinoma were made based on biopsies obtained via bronchoscopy. Five tumors were classified as intraluminal type and successfully eradicated by carbon dioxide cryotherapy and argon plasma coagulation under bronchoscopy. The other tumor in patient 3 was classified as the mixture type and could not be removed by a bronchoscopic, so left upper lobectomy was performed. For each patient, interventional procedures were conducted on the average for 6 times. No recurrence was detected by bronchoscopic inspections or computed tomography scans during follow-ups for 16-72 months. CONCLUSIONS: Multiple bronchoscopic procedures, as alternative treatments, are effective in removing bronchial mucoepidermoid carcinoma mucoepidermoid carcinoma in children without any major complications.