Abstract
BackgroundWhile treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC.MethodsTo study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-β stimulation.ResultssiRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells.ConclusionThese results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0284-4) contains supplementary material, which is available to authorized users.
Highlights
While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in Head and neck squamous cell carcinoma (HNSCC) is limited
The distant metastatic potential of 26 HNSCC lines in an experimental lung metastatic mouse model Twenty-six HNSCC cell lines showed a wide spectrum of distant metastatic potential in vivo
Survival curves for mice injected with each of the 26 HNSCC cell lines are shown in Additional file 3: Figure S1
Summary
While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. The survival of patients with HNSCC has not dramatically improved over the past several decades despite advances in multidisciplinary treatment [2, 3]. This is because of many newly diagnosed HNSCC patients present with advanced stage disease at diagnosis, and partly due to our inability to control and our poor understanding of the regional and distant spread of this disease. The activation of AP-1 has been reported to play a critical role in the invasive growth and metastasis of human cancers, the significance of AP-1 in metastasis in HNSCC is not yet fully understood
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