RRC ID 45484
Author Saito T, Kasamatsu A, Ogawara K, Miyamoto I, Saito K, Iyoda M, Suzuki T, Endo-Sakamoto Y, Shiiba M, Tanzawa H, Uzawa K.
Title Semaphorin7A Promotion of Tumoral Growth and Metastasis in Human Oral Cancer by Regulation of G1 Cell Cycle and Matrix Metalloproteases: Possible Contribution to Tumoral Angiogenesis.
Journal PLoS ONE
Abstract BACKGROUND: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. 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).
METHODS:We 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.
RESULTS:SEMA7A 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).
CONCLUSION:Our 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.
Volume 10(9)
Pages e0137923
Published 2015
DOI 10.1371/journal.pone.0137923
PII PONE-D-15-23388
PMID 26378920
PMC PMC4574527
MeSH Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / pathology Cell Cycle Checkpoints / genetics Cell Line, Tumor Cell Movement / genetics Cell Proliferation / genetics* Cyclin D1 / genetics Cyclin E / genetics Cyclin-Dependent Kinase Inhibitor p21 / genetics Cyclin-Dependent Kinase Inhibitor p27 / genetics Cyclin-Dependent Kinases / genetics Down-Regulation / genetics G1 Phase / genetics* Humans MAP Kinase Signaling System / genetics Matrix Metalloproteinases / genetics* Mouth Neoplasms / genetics* Mouth Neoplasms / pathology Neoplasm Invasiveness / genetics Neoplasm Invasiveness / pathology Neoplasm Metastasis / genetics* Neoplasm Metastasis / pathology Neovascularization, Pathologic / genetics* Neovascularization, Pathologic / pathology Proto-Oncogene Proteins c-akt / genetics Semaphorins / genetics* Up-Regulation / genetics
IF 2.776
Times Cited 8
Human and Animal Cells