title: CD44 targets Na(+)/H(+) exchanger 1 to mediate MDA-MB-231 cells' metastasis via the regulation of ERK1/2.
abstract: BACKGROUND
  CD44, a transmembrane glycoprotein expressed in a variety of cells and tissues, has been implicated in tumour metastasis. But the molecular mechanisms of CD44-mediated tumour cell metastasis remain to be elucidated.
  
  
  METHODS
  The downregulation of CD44 was determined by immunofluorescence. Moreover, the motility of breast cancer cells was detected by wound-healing and transwell experiments. Then the spontaneous metastasis of CD44-silenced MDA-MB-231 cells was tested by histology with BALB/c nude mice.
  
  
  RESULTS
  A positive correlation between CD44 and Na(+)/H(+) exchanger isoform 1 (NHE1) was found in two breast cancer cells. CD44 downregulation could inhibit the metastasis of MDA-MB-231 cells and the expressions of Na(+)/H(+) exchanger 1. Moreover, CD44 overexpression upregulated the metastasis of MCF-7 cells, but the elevated metastatic ability was then inhibited by Cariporide. Interestingly, during these processes only the p-ERK1/2 was suppressed by CD44 downregulation and the expression of matrix metalloproteinases and metastatic capacity of MDA-MB-231 cells were greatly inhibited by the MEK1 inhibitor PD98059, which even had a synergistic effect with Cariporide. Furthermore, CD44 downregulation inhibits breast tumour outgrowth and spontaneous lung metastasis.
  
  
  CONCLUSIONS
  Taken together, this work indicates that CD44 regulates the metastasis of breast cancer cells through regulating NHE1 expression, which could be used as a novel strategy for breast cancer therapy.
authors.affiliation: 1] State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China [2] Department of Neurology, Tianjin Medical University General Hospital; Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Anshan Road, Tianjin 300052, China.
authors.forename: G
authors.initials: G
authors.lastname: Chang
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: T
authors.initials: T
authors.lastname: Pang
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006146:Guanidines / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000378:metabolism*; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D014945:Wound Healing
chemical_list: D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D005419:Flavonoids; D006146:Guanidines; D018960:Hyaluronan Receptors; D047428:Protein Kinase Inhibitors; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one