Abstract
BackgroundSemaphorins (SEMAs) consist of a large family of secreted and membrane-anchored proteins that are important in neuronal pathfinding and axon guidance in selected areas of the developing nervous system. Of them, SEMA7A has been reported to have a chemotactic activity in neurogenesis and to be an immunomodulator; however, little is known about the relevance of SEMA7A in the behaviors of oral squamous cell carcinoma (OSCC).MethodsWe evaluated SEMA7A expression in OSCC-derived cell lines and primary OSCC samples using quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and semiquantitative immunohistochemistry (sq-IHC). In addition, SEMA7A knockdown cells (shSEMA7A cells) were used for functional experiments, including cellular proliferation, invasiveness, and migration assays. We also analyzed the clinical correlation between SEMA7A status and clinical behaviors in patients with OSCC.ResultsSEMA7A mRNA and protein were up-regulated significantly (P<0.05) in OSCC-derived cell lines compared with human normal oral keratinocytes. The shSEMA7A cells showed decreased cellular growth by cell-cycle arrest at the G1 phase, resulting from up-regulation of cyclin-dependent kinase inhibitors (p21Cip1 and p27Kip1) and down-regulation of cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6); and decreased invasiveness and migration activities by reduced secretion of matrix metalloproteases (MMPs) (MMP-2, proMMP-2, pro-MMP-9), and expression of membrane type 1- MMP (MT1-MMP). We also found inactivation of the extracellular regulated kinase 1/2 and AKT pathways, an upstream molecule of cell-cycle arrest at the G1 phase, and reduced secretion of MMPs in shSEMA7A cells. sq-IHC showed that SEMA7A expression in the primary OSCCs was significantly (P = 0.001) greater than that in normal counterparts and was correlated with primary tumoral size (P = 0.0254) and regional lymph node metastasis (P = 0.0002).ConclusionOur data provide evidence for an essential role of SEMA7A in tumoral growth and metastasis in OSCC and indicated that SEMA7A may play a potential diagnostic/therapeutic target for use in patients with OSCC.
Highlights
Semaphorins (SEMAs), secreted and membrane-associated proteins, provide environmental cues to mediate diverse developmental processes including neuronal cellular migration, axon guidance, vasculogenesis, branching morphogenesis, and cardiac organogenesis [1]
SEMA7A mRNA and protein were up-regulated significantly (P
We found inactivation of the extracellular regulated kinase 1/2 and AKT pathways, an upstream molecule of cell-cycle arrest at the G1 phase, and reduced secretion of matrix metalloproteases (MMPs) in shSEMA7A cells. semiquantitative immunohistochemistry (sq-IHC) showed that SEMA7A expression in the primary OSCCs was significantly (P = 0.001) greater than that in normal counterparts and was correlated with primary tumoral size (P = 0.0254) and regional lymph node metastasis (P = 0.0002)
Summary
Semaphorins (SEMAs), secreted and membrane-associated proteins, provide environmental cues to mediate diverse developmental processes including neuronal cellular migration, axon guidance, vasculogenesis, branching morphogenesis, and cardiac organogenesis [1]. SEMAs are expressed in the immune response systems, including B cells, T cells, natural killer cells, and macrophages, and have been implicated in regulation of organogenesis, angiogenesis, apoptosis, and neoplasia [2]. SEMA4-7 exist primarily as membrane-bound forms, whereas SEMA3 is secreted as a soluble molecule. Diffusible SEMAs can elicit autocrine/ paracrine signaling, while membrane-bound family members can mediate short-range juxtacrine signals. Semaphorins (SEMAs) consist of a large family of secreted and membrane-anchored proteins that are important in neuronal pathfinding and axon guidance in selected areas of the developing nervous system. SEMA7A has been reported to have a chemotactic activity in neurogenesis and to be an immunomodulator; little is known about the relevance of SEMA7A in the behaviors of oral squamous cell carcinoma (OSCC)
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