title: SHP2, SOCS3 and PIAS3 Expression Patterns in Medulloblastomas: Relevance to STAT3 Activation and Resveratrol-Suppressed STAT3 Signaling.
abstract: BACKGROUND
  Activated STAT3 signaling is critical for human medulloblastoma cells. SHP2, SOCS3 and PIAS3 are known as the negative regulators of STAT3 signaling, while their relevance to frequent STAT3 activation in medulloblastomas remains unknown.
  
  
  METHODS
  Tissue microarrays were constructed with 17 tumor-surrounding noncancerous brain tissues and 61 cases of the classic medulloblastomas, 44 the large-cell medulloblastomas, and 15 nodular medulloblastomas, which were used for immunohistochemical profiling of STAT3, SHP2, SOCS3 and PIAS3 expression patterns and the frequencies of STAT3 nuclear translocation. Three human medulloblastoma cell lines (Daoy, UW228-2 and UW228-3) were cultured with and without 100 μM resveratrol supplementation. The influences of resveratrol in SHP2, SOCS3 and PIAS3 expression and SOCS3 knockdown in STAT3 activation were analyzed using multiple experimental approaches.
  
  
  RESULTS
  SHP2, SOCS3 and PIAS3 levels are reduced in medulloblastomas in vivo and in vitro, of which PIAS3 downregulation is more reversely correlated with STAT3 activation. In resveratrol-suppressed medulloblastoma cells with STAT3 downregulation and decreased incidence of STAT3 nuclear translocation, PIAS3 is upregulated, the SHP2 level remains unchanged and SOCS3 is downregulated. SOCS3 proteins are accumulated in the distal ends of axon-like processes of resveratrol-differentiated medulloblastoma cells. Knockdown of SOCS3 expression by siRNA neither influences cell proliferation nor STAT3 activation or resveratrol sensitivity but inhibits resveratrol-induced axon-like process formation.
  
  
  CONCLUSIONS
  Our results suggest that (1) the overall reduction of SHP2, SOCS3 and PIAS3 in medulloblastoma tissues and cell lines; (2) the more inverse relevance of PIAS3 expression with STAT3 activation; (3) the favorable prognostic values of PIAS3 for medulloblastomas and (4) the involvement of SOCS3 in resveratrol-promoted axon regeneration of medulloblastoma cells.
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. goodluck_licong@163.com.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. lihongmcn@dlmedu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. zhangpenggirl821@sina.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. yulijundl1963@163.com.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yu
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. huangtianmiao6688@aliyun.com.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Huang
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. songxue0214@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Song
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. kqydl@sina.com.
authors.forename: Qing-You
authors.initials: QY
authors.lastname: Kong
authors.affiliation: Department of Orthopedic Surgery, Second Hospital of Dalian Medical University, Dalian 116011, China. jldongdl@aliyun.com.
authors.forename: Jian-Li
authors.initials: JL
authors.lastname: Dong
authors.affiliation: Department of Orthopedic Surgery, Second Hospital of Dalian Medical University, Dalian 116011, China. delaho@126.com.
authors.forename: Pei-Nan
authors.initials: PN
authors.lastname: Li
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, Dalian Medical University, Dalian 116044, China. jialiudl@aliyun.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D000071223:Suppressor of Cytokine Signaling 3 Protein; D000077185:Resveratrol
keywords: PIAS3; STAT3 negative regulators; STAT3 signaling; medulloblastoma; resveratrol