title: Metastasis suppressor Nm23-H1 inhibits STAT3 signaling via a negative feedback mechanism.
abstract: Persistent STAT3 activation is a critical event in tumorigenesis and metastatic progression. Recent studies have found higher levels of STAT3 in metastatic tissues than in primary tumor tissues. We speculated that such increased STAT3 activity might be attributed to a loss of function or reduction in expression of metastasis inhibitory protein during cancer progression, and we therefore examined the role of tumor metastasis-suppressor nm23-H1 in the activation of STAT3 in the A549 lung cancer cell line. We found that IL-6-dependent induction of tyrosine phosphorylation and activation of STAT3 were influenced by nm23-H1 inhibition. IL-6-induced STAT3(Tyr705) phosphorylation was significantly enhanced in A549 cells transfected with siRNA specific for nm23-H1, and the effect of nm23-H1 depletion on IL-6-induced STAT3(Tyr705) phosphorylation was reversed by ectopic expression of shRNA-resistant nm23-H1 protein. Moreover, STAT3 directly bound to the STAT3 binding site on the nm23-H1 promoter and activated its expression. Thus, we have identified a new feedback mechanism that might provide insight into an in-built metastasis-suppression function in tumor cells and which could be a logical new target for treatment of early metastatic disease.
authors.affiliation: Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Anshan Road No 154, Heping District, Tianjin 300052, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wu
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Rongzhi
authors.initials: R
authors.lastname: Zhao
authors.forename: Daxing
authors.initials: D
authors.lastname: Zhu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005246:Feedback; D006801:Humans; D016297:Mutagenesis, Site-Directed; D054778:NM23 Nucleoside Diphosphate Kinases / Q000502:physiology*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D054778:NM23 Nucleoside Diphosphate Kinases; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C517938:NME1 protein, human