Abstract
Dynamin 3 (DNM3) has gained increased attention ever since its potential as a tumor suppressor was reported. However, its action in lung cancer (LC) is undefined. In this study, the role of DNM3 in LC development was investigated. DNM3 expression was found to be downregulated in tumors of patients with LC, especially those with metastasis. The DNM3 downregulation enhanced the proliferative and metastatic ability of LC cells, whereas its upregulation had the opposite effects. In vivo xenograft experiments confirmed that lung tumors with lower DNM3 expression had higher growth and metastatic abilities. Mechanistic studies revealed that DNM3 interacts with growth factor receptor-bound protein 2 (GBR2), thereby interrupting tyrosine-protein kinase Met (c-MET)–GBR2–signal transducer and activator of transcription 3 (STAT3) complex formation, which suppressed STAT3 activation. Therefore, the absence of DNM3 frees GBR2 to activate STAT3, which regulates the expression of genes related to LC proliferation and metastasis (e.g., cyclin D1 and Snail family transcriptional repressor 1). Additionally, the c-MET inhibitor crizotinib effectively suppressed LC cell proliferation and migration in vitro and in vivo, even with DNM3 depleted. Therefore, our study has demonstrated the antitumor effect of DNM3 in LC and suggests that the inhibition of c-MET might be a promising strategy for treating those LC patients with low DNM3 expression.
Highlights
Lung cancer (LC) is a common malignancy worldwide with a high mortality rate, accounting for 27% of cancer−related deaths in the United States in 2018 (Bray et al, 2018; Siegel et al, 2018)
The RT-PCR analysis revealed that the Dynamin 3 (DNM3) was lower in the lung cancer (LC) tumors at the mRNA level (Figure 1A), the mRNA levels were higher in LC tissues than in adjacent normal lung tissue for many patients
This study showed that DNM3 was downregulated in LC tissue cells and that the downregulation of this enzyme promoted the proliferative and metastatic capacities of the cells by increasing cyclin D1 (CCND1) and Snail family transcriptional repressor 1 (SNAI1) expression
Summary
Lung cancer (LC) is a common malignancy worldwide with a high mortality rate, accounting for 27% of cancer−related deaths in the United States in 2018 (Bray et al, 2018; Siegel et al, 2018). The significant progress made in the treatment of non-small-cell lung cancer (NSCLC) through individualized therapy and immunotherapy is very effective in some patients, the 5−year overall survival (OS) of patients with different stages of NSCLC is still only 18%, and that of patients with metastatic tumor is only 5% (Siegel et al, 2018). Because of the high incidence and mortality rate of LC, there is an urgent need to identify the key molecular predictors of LC pathogenesis. The activity of DNM3 in LC is still not yet understood, and its precise function as a tumor suppressor remains unclear
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