title: Plasminogen Activator Inhibitor-2 Plays a Leading Prognostic Role among Protease Families in Non-Small Cell Lung Cancer.
abstract: BACKGROUND
  In lung cancer, uPA, its receptor (uPAR), and the inhibitors PAI-1 and PAI-2 of the plasminogen activator family interact with MMP-2 and MMP-9 of the MMP family to promote cancer progression. However, it remains undetermined which of these markers plays the most important role and may be the most useful indicator to stratify the patients by risk.
  
  
  METHODS
  We determined the individual prognostic value of these 6 markers by analyzing a derivation cohort with 98 non-small cell lung cancer patients by immunohistochemical staining. The correlation between the IHC expression levels of these markers and disease prognosis was investigated, and an immunohistochemical panel for prognostic prediction was subsequently generated through prognostic model analysis. The value of the immunohistochemical panel was then verified by a validation cohort with 91 lung cancer patients.
  
  
  RESULTS
  In derivation cohort, PAI-2 is the most powerful prognostic factor (HR = 2.30; P = 0.001), followed by MMP-9 (HR = 2.09; P = 0.019) according to multivariate analysis. When combining PAI-2 and MMP-9, the most unfavorable prognostic group (low PAI-2 and high MMP-9 IHC expression levels) showed a 6.40-fold increased risk of a poor prognosis compared to the most favorable prognostic group (high PAI-2 and low MMP-9 IHC expression levels). PAI-2 and MMP-9 IHC panel could more precisely identify high risk patients in both derivation and validation cohort.
  
  
  CONCLUSIONS
  We revealed PAI-2 as the most powerful prognostic marker among PA and MMP protease family even after considering their close relationships with each other. By utilizing a combination of PAI-2 and MMP-9, more precise prognostic information than merely using pathological stage alone can be obtained for lung cancer patients.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Su
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan; The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
authors.forename: Jean
authors.initials: J
authors.lastname: Chiou
authors.affiliation: The Ph.D. Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chi
authors.affiliation: Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jih-Jong
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: The Ph.D. Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
authors.forename: Alex T H
authors.initials: AT
authors.lastname: Wu
authors.affiliation: Institute of Clinical Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D010447:Peptide Hydrolases / Q000378:metabolism*; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D017396:Plasminogen Activator Inhibitor 2; D010447:Peptide Hydrolases; D020780:Matrix Metalloproteinase 9