title: HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells.
abstract: OBJECTIVE
  Human epidermal growth factor receptor 2 (HER2) (neu/ERBB2) is overexpressed on many types of cancer cells, including gastric cancer cells; HER2 overexpression has been associated with metastasis and poor prognosis. We investigated the mechanisms by which HER2 regulates cell migration and invasion.
  
  
  METHODS
  HER2 expression or activity was reduced in gastric cancer cell lines using small interfering RNAs or the monoclonal antibody, trastuzumab. We identified proteins that interact with HER2 or microRNAs (miRNAs) involved in HER2 signaling. We used various software programs to identify miRNAs that regulate factors in the HER2 signaling pathway. We analyzed expression patterns of these miRNAs in gastric cancer cell lines and tumor samples from patients.
  
  
  RESULTS
  We found that CD44 binds directly to HER2, which up-regulates the expression of metastasis-associated protein-1, induces deacetylation of histone H3 lysine 9, and suppresses transcription of microRNA139 (miR-139) to inhibit expression of its target gene, C-X-C chemokine receptor type 4 (CXCR4). Knockdown of HER2 and CD44 reduced invasive activity of cultured gastric cancer cells and suppressed tumor growth in nude mice. Lymph node metastasis was associated with high levels of HER2, CD44, and CXCR4, and reduced levels of miR-139 in human metastatic gastric tumors. Cultures of different types of metastatic cancer cells with histone deacetylase inhibitors and/or DNA methyltransferase resulted in up-regulation of miR-139.
  
  
  CONCLUSIONS
  HER2 interaction with CD44 up-regulates CXCR4 by inhibiting expression of miR-139, at the epigenetic level, in gastric cancer cells. These findings indicate how HER2 signaling might promote gastric tumor progression and metastasis.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Bao
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Fu
authors.forename: Qiao-Sheng
authors.initials: QS
authors.lastname: Xie
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Zhang-Yan
authors.initials: ZY
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Meng
authors.forename: Xin-Ling
authors.initials: XL
authors.lastname: Ren
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Bo-Quan
authors.initials: BQ
authors.lastname: Jin
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Yao
authors.forename: Rui-An
authors.initials: RA
authors.lastname: Wang
authors.forename: Dai-Ming
authors.initials: DM
authors.lastname: Fan
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002465:Cell Movement; D017931:DNA Primers / Q000737:chemistry; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D021141:Nucleic Acid Amplification Techniques; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D018960:Hyaluronan Receptors; D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; C497483:CD44 protein, human; C555098:MIRN139 microRNA, human