title: Integrin αvβ6 and matrix metalloproteinase 9 correlate with survival in gastric cancer.
abstract: OBJECTIVE
  To investigate the expression of integrin αvβ6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients.
  
  
  METHODS
  Immunohistochemistry was used to determine the expressions of integrin αvβ6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ(2) test and Fisher's exact test. Expression correlation of αvβ6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvβ6 and MMP-9 levels (that is, both markers positive, both markers negative, αvβ6 positive with MMP-9 negative, and αvβ6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis.
  
  
  RESULTS
  The expressions of integrin αvβ6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvβ6 expression, and 42.06% for MMP-9 expression. The expression of αvβ6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvβ6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvβ6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvβ6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvβ6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvβ6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvβ6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007).
  
  
  CONCLUSIONS
  The expression of αvβ6 and MMP-9 are closely correlated, and the combinational pattern of αvβ6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Pei-Long
authors.initials: PL
authors.lastname: Lian
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Guang-Yun
authors.initials: GY
authors.lastname: Yang
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Zhao-Yang
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Yue-Guang
authors.initials: YG
authors.lastname: Chen
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Zhuo-Nan
authors.initials: ZN
authors.lastname: Zhuang
authors.affiliation: Pei-Long Lian, Rui Zhao, Zhao-Yang Zhang, Yue-Guang Chen, Ke-Sen Xu, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Ke-Sen
authors.initials: KS
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000032:analysis*; D053208:Kaplan-Meier Estimate; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D016023:Integrins; C073878:integrin alphavbeta6; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Gastric cancer; Integrin αvβ6; Matrix metalloproteinase 9; Prognosis; Survival