title: Protumoral roles of melanoma inhibitory activity 2 in oral squamous cell carcinoma.
abstract: BACKGROUND
  The role of melanoma inhibitory activity 2 (MIA2) was examined in human oral squamous cell carcinoma (OSCC).
  
  
  METHODS
  MIA2 role was examined by immunohistochemistry of human OSCCs and knockdown studies using human 3 OSCC cell lines with MIA2 expression.
  
  
  RESULTS
  MIA2 expression was observed in 62 (66.7%) of 93 OSCCs and was associated with tumour expansion and nodal metastasis. Melanoma inhibitory activity 2 expression was inversely correlated with intratumoral infiltration of lymphocytes. Invasion and anti-apoptotic survival were reduced by MIA2 knockdown in HSC3 cells. MOLT-3 lymphocytes infiltrating the HSC3 cell layer was enhanced by MIA2 knockdown or MIA2 depletion with the antibody. In HSC3 cells, MIA2 knockdown decreased the expressions of vascular endothelial growth factor (VEGF), VEGF-C, and VEGF-D. The downregulation of VEGF-C and -D was caused by inhibition of p38 and extracellular signal-regulated kinase (ERK)1/2, respectively. Melanoma inhibitory activity 2 was co-precipitated with integrin α4 andα5 in HSC3 cells. Integrin α4 knockdown decreased p38 phosphorylation and increased apoptosis, whereas integrin α5 knockdown decreased c-Jun N-terminal kinase (JNK) phosphorylation and apoptosis. Inhibition of JNK decreased apoptosis in the HSC3 cells.
  
  
  CONCLUSIONS
  These findings suggest that the roles of MIA2 might be based on the variety of the integrins and the subtypes of mitogen-activated protein kinase.
authors.affiliation: Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Kirita
authors.forename: T
authors.initials: T
authors.lastname: Sasahira
authors.forename: H
authors.initials: H
authors.lastname: Ohmori
authors.forename: S
authors.initials: S
authors.lastname: Matsushima
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: A K
authors.initials: AK
authors.lastname: Bosserhoff
authors.forename: H
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009062:Mouth Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; C109278:MIA2 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; C467486:VEGFC protein, human; C579459:VEGFD protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D020928:Mitogen-Activated Protein Kinases