title: Tissue inhibitor of metalloproteinases-4 (TIMP-4) regulates stemness in cervical cancer cells.
abstract: Tissue inhibitor of metalloproteinase-4 (TIMP-4) belongs to a family of extracellular matrix (ECM) metalloproteinases inhibitors that are overexpressed in several cancers. However, the role of TIMP-4 during carcinogenesis is poorly understood. To evaluate TIMP-4 functions in carcinogenesis, stably transfected cells overexpressing this tissue inhibitor were used. Xenograft tumor growth, stem cell enrichment, colony formation, and gene regulation were investigated. Microarrays and in silico analysis were carried out to elucidate TIMP-4 molecular mechanisms. In the present report, we show that in nude mice, cervical cancer cells that overexpress TIMP-4 formed tumors faster than control cell-derived tumors. Furthermore, in vivo limiting dilution assays showed that fewer TIMP-4 overexpressing cells are needed for tumor formation. In vitro analyses demonstrated that TIMP-4 overexpression or exposure to human recombinant TIMP-4 (hrTIMP4) caused an enrichment of the tumor progenitor cell (TPC) population. Accordingly, genome-wide expression and signaling pathway analyses showed that hrTIMP-4 modulated cell survival, cell proliferation, inflammation, and epithelial-mesenchymal transition (EMT) signaling networks. Notably, NFκB signaling pathway appeared to be globally activated upon hrTIMP-4 treatment. Overall, this report provides the first example that TIMP-4 regulates carcinogenesis through enriching the TPC population in cervical cancer cells. Understanding TIMP-4 effects on tumorigenesis may provide clues for future therapies design. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Epigenetics Laboratory, Medical Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Floria
authors.initials: F
authors.lastname: Lizarraga
authors.affiliation: Functional Genomics Laboratory, Basic Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Magali
authors.initials: M
authors.lastname: Espinosa
authors.affiliation: Functional Genomics Laboratory, Basic Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Gisela
authors.initials: G
authors.lastname: Ceballos-Cancino
authors.affiliation: Epigenetics Laboratory, Medical Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Karla
authors.initials: K
authors.lastname: Vazquez-Santillan
authors.affiliation: Functional Genomics Laboratory, Basic Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bahena-Ocampo
authors.affiliation: Functional Genomics Laboratory, Basic Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Angela
authors.initials: A
authors.lastname: Schwarz-Cruz Y Celis
authors.affiliation: Functional Genomics Laboratory, Basic Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Vega-Gordillo
authors.affiliation: Pharmacology Laboratory, Basic Research Subdirection, National Institute of Cancerology, Ciudad de México, Mexico.
authors.forename: Patricia
authors.initials: P
authors.lastname: Garcia Lopez
authors.affiliation: Epigenetics Laboratory, Medical Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Vilma
authors.initials: V
authors.lastname: Maldonado
authors.affiliation: Functional Genomics Laboratory, Basic Research Subdirection, National Institute of Genomic Medicine, Ciudad de México, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
mesh_terms: D000818:Animals; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D016328:NF-kappa B; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4
keywords: NFκB; TIMP-4; gene regulation; tumor progenitor cells