title: Signal transducer and activator of transcription-3 activation contributes to high tissue inhibitor of metalloproteinase-1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.
abstract: The tissue inhibitor of metalloproteinase-1 (TIMP1) is expressed in a subset of malignant lymphomas and can inhibit tumor spread and promote cell survival. Recent data suggest that TIMP1 expression may be regulated by signal transducer and activator of transcription (STAT)-3. Thus, we tested the hypothesis that TIMP1 expression is related to STAT3 activation in lymphomas, with a focus on anaplastic large cell lymphomas (ALCLs), which are known to express high levels of phosphorylated/active STAT3 (pSTAT3). Specific inhibition of STAT3 with a dominant-negative construct led to concentration-dependent down-regulation of TIMP1 expression in two anaplastic lymphoma kinase (ALK)(+) ALCL cell lines, Karpas 299 and SU-DHL-1. Using cDNA microarrays, ALK(+) ALCL cell lines consistently expressed the highest TIMP1 level among 29 lymphoma cell lines of various subtypes. The association between TIMP1 expression and high level of STAT3 activation was validated by Western blots and immunostaining using antibodies specific for pSTAT3 and TIMP1. We further evaluated the relationship between TIMP1 expression and STAT3 activation in 43 ALCL tumors (19 ALK(+) and 24 ALK(-)) using immunohistochemistry and a tissue microarray. The TIMP1(+) group had a mean of 64% pSTAT3(+) cells as compared to 23% pSTAT3(+) cells in the TIMP1(-) group (P = 0.002). As expected, TIMP1 positivity was higher in the ALK(+) group (15 of 19, 79%) compared with the ALK(-) group (5 of 24, 21%; P = 0.0002) because NPM-ALK restricted to ALK(+) tumors was previously shown to activate STAT3. In conclusion, STAT3 directly contributes to the high level of TIMP1 expression in ALK(+) ALCL, and TIMP1 expression correlates with high level of STAT3 activation in ALCL. TIMP1, as a downstream target of STAT3, may mediate the anti-apoptotic effects of STAT3.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. raymondmail_65@yahoo.com
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Latha
authors.initials: L
authors.lastname: Ramdas
authors.forename: Andre H
authors.initials: AH
authors.lastname: Goy
authors.forename: Cathy
authors.initials: C
authors.lastname: Cutler
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Keita
authors.initials: K
authors.lastname: Kunisada
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: Frederic
authors.initials: F
authors.lastname: Gilles
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis*; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D015534:Trans-Activators; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases