title: Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis.
abstract: OBJECTIVE
  Matrix metalloproteinase (MMP)-2 and MMP-9 are considered to play an important role in the metastasis of malignant tumors. Membrane type 1-MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2) are essential factors for the activation of pro-MMP-2. There are some reports about expressions of MMP family in relationship to clinical features of head and neck squamous cell carcinoma (SCC), but the results were not uniform and the prognostic value of their expressions remains unclear.
  
  
  METHODS
  The study group consisted of 53 Japanese patients with oral SCC of early stage (T(1-2)N(0)M(0)). Expressions of MMP-2, MMP-9, MT1-MMP, and TIMP-2 were examined using immunohistological methods on the sections of tumor biopsy samples. The intensity of MMP expression was categorized into four grades (score 0-3) by semiquantitative analysis using a computer with NIH image, and correlation between this grade and clinical aspects such as tumor recurrence, metastasis, and prognosis were examined.
  
  
  RESULTS
  The expression score of MMP-2 correlated with that of MMP-9 (r = 0.291; P = 0.036), MT1-MMP (r = 0.286; P = 0.039), and TIMP-2 (r = 0.257; P = 0.050). Patients who developed regional lymph node and/or distant metastasis showed significantly higher scores in the expressions of MMP-9 and TIMP-2 than patients without any tumor metastases (P = 0.036 and P = 0.043, respectively). Kaplan-Meier analyses as well as univariate analyses using the Cox proportional hazards model showed that expression of MMP-9 (P = 0.0143 and P = 0.0418, respectively) and marked expression of TIMP-2 (P < 0.0001 and P = 0.0004, respectively) correlated with worse-cause-specific survival. Multivariate analysis confirmed that marked expression of TIMP-2 was the only independent factor for cause-specific death (hazard ratio, 7.543; confidence interval, 1.693-33.610; P = 0.0080).
  
  
  CONCLUSIONS
  Expressions of MMP-9 and TIMP-2 have predictive value for tumor metastases and cause-specific survival. High expression of TIMP-2 is the most independent factor for worse prognosis in early-stage oral SCC.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical College, Asahikawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katayama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Bandoh
authors.forename: Kan
authors.initials: K
authors.lastname: Kishibe
authors.forename: Miki
authors.initials: M
authors.lastname: Takahara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogino
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nonaka
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000378:metabolism; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D016896:Treatment Outcome
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9