RESUMO
BACKGROUND/AIMS: To investigate the clinical significance and functional mechanisms of membrane-associated RING-CH protein 9 (MARCH9) in lung adenocarcinoma (LAC). METHODS: Immunohistochemistry staining was performed to explore the expression of MARCH9 in LAC tissues and adjacent normal lung tissues. Patients' prognosis was evaluated using overall survival. The prognostic role of MARCH9 was tested with univariate and multivariate analyses. To confirm the effect of MARCH9 in cell proliferation and invasion, overexpression of MARCH9 was induced in two LAC cell lines. Cell cycle, apoptosis, migration, invasion, and immunoprecipitation experiments were performed to further explore the signaling pathways involved. RESULTS: Analysis of a series of 143 clinical samples revealed that MARCH9 was down-regulated in tumor tissues compared with normal lung tissues, and this was closely associated with lymph node metastasis (P = 0.004). Univariate and multivariate analyses indicated that MARCH9 was an independent prognostic biomarker for LAC; low MARCH9 expression indicated poor overall survival. Cellular studies with A549 and H1299 cells demonstrated that MARCH9 can attenuate tumor migration and invasion but had little effect on cell cycle or apoptosis. Moreover, an interaction between MARCH9 and ICAM-1 protein was identified, and overexpression of MARCH9 was found to attenuate the oncogenic effect of ICAM-1, suggesting that MARCH9 may inhibit tumor progression by downregulating ICAM-1 signaling. CONCLUSION: MARCH9 downregulation in LAC tissues correlated with poor clinical outcomes. MARCH9 may serve as a novel biomarker and potential therapeutic target for LAC.
Assuntos
Adenocarcinoma/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Adulto , Idoso , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Feminino , Humanos , Molécula 1 de Adesão Intercelular/genética , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Metástase Linfática , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genéticaRESUMO
Lung cancer was the most commonly diagnosed cancer in 2008 worldwide. The level of fibulin-3 expression was found to be decreased in many cancer types due to aberrant promoter methylation and is correlated with poor survival of patients. However, the role of fibulin-3 and which form of fibulin-3 is expressed in lung cancer cells remain unclear. Therefore, pathologic and functional studies were carried out to determine the role of fibulin-3 in suppressing lung cancer both in vivo and in vitro. In the present study, we found that the levels of fibulin-3 mRNA and protein were lower in cancer tissues than in normal tissues. Downregulation of fibulin-3 mRNA in tumor tissues was associated with an increase in fibulin-3 promoter methylation. Circulating fibulin-3 was significantly associated with tumor progression, survival rate of lung cancer patients, and the number of circulating tumor cells (CTCs). To examine the effects of exogenous expression of fibulin-3 in vitro, lung cancer A549 cells were transfected with the pEGFP-C1-fibulin-3 expression vector. Relative to the untreated cells, fibulin-3-expressing cells exhibited lower proliferation and mobility as determined by MTT and Transwell assays, respectively. To conclude, our results suggest that fibulin-3 negatively modulates the invasiveness of lung cancer cells via regulation of p38-MAPK and MMP-2/9.