title: SEMA4b inhibits MMP9 to prevent metastasis of non-small cell lung cancer.
abstract: Semaphorin 4B (SEMA4b) has been shown to play a substantial role in the invasion of non-small cell lung cancer (NSCLC). However, the regulation mechanism of SEMA4b is largely elusive. Here, we reported significant decrease in SEMA4b level and significant increase in MMP9 level in NSCLC compared with the adjacent normal tissue from the same patient. We thus used two human NSCLC lines, A549 and Calu-3, to examine whether SEMA4b may affect the expression of MMP9 in NSCLC. We found that overexpression of SEMA4b significantly decreased MMP9 level, while SEMA4b inhibition significantly increased MMP9 level. The adapted MMP9 levels affected the potential of NSCLC invasiveness correspondingly. To define the signal transduction cascades downstream of SEMA4b for regulation of MMP9 expression, we inhibited PI3K, ERK/MAPK, or JNK signaling pathway in SEMA4b knockout NSCLC and found that only inhibition of PI3K signaling pathway significantly decreased MMP9 activation. Our data thus suggest that SEMA4b may activate PI3K signaling pathway to promote MMP9 expression, which subsequently increases metastasis of NSCLC. Our study thus highlights SEMA4b as a novel therapeutic target for NSCLC.
authors.affiliation: Shanghai Lung Cancer Center, Shanghai Chest Hospital Affiliated To Shanghai Jiaotong University, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jian
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; C574096:SEMA4A protein, human; D039961:Semaphorins; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
references.citation: Tumour Biol. 2014 Jul;35(7):6679-85
references.pmid: 24705862
references.citation: J Biol Chem. 2014 Jun 27;289(26):17971-9
references.pmid: 24825896
references.citation: J Neurosci. 2003 Aug 20;23(20):7602-9
references.pmid: 12930799
references.citation: Mol Cell Biol. 2005 Aug;25(16):6889-98
references.pmid: 16055703
references.citation: Tumour Biol. 2014 May;35(5):4949-55
references.pmid: 24474252
references.citation: J Exp Med. 2010 Dec 20;207(13):2943-57
references.pmid: 21098092
references.citation: Adv Exp Med Biol. 2007;600:24-37
references.pmid: 17607944
references.citation: Dig Dis Sci. 2013 Aug;58(8):2197-204
references.pmid: 23661031
references.citation: Tumour Biol. 2014 Jul;35(7):6673-8
references.pmid: 24705809
references.citation: FEBS Lett. 2005 Jul 4;579(17):3821-8
references.pmid: 15978582
references.citation: Oncogene. 2007 Jun 7;26(27):4025-31
references.pmid: 17213806
references.citation: Dev Neurobiol. 2008 Jun;68(7):926-33
references.pmid: 18327764
references.citation: Tumour Biol. 2014 Sep;35(9):8653-8
references.pmid: 24867100