Tissue inhibitor of metalloproteinases-4 (TIMP-4) regulates stemness in cervical cancer cells

• Published in: Molecular carcinogenesis 2016-12, Vol.55 (12), p.1952-1961
• Main Authors: Lizarraga, Floria, Espinosa, Magali, Ceballos-Cancino, Gisela, Vazquez-Santillan, Karla, Bahena-Ocampo, Ivan, Schwarz-Cruz y Celis, Angela, Vega-Gordillo, Montserrat, Garcia Lopez, Patricia, Maldonado, Vilma, Melendez-Zajgla, Jorge
• Format: Article
• Language: English
• Subjects: Animals; Cervical cancer; Cervix Uteri - metabolism; Cervix Uteri - pathology; Enzymes; Extracellular matrix; Female; Gene Expression Regulation, Neoplastic; gene regulation; HeLa Cells; Humans; Mice; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-kappa B - metabolism; NFκB; Proteins; Signal Transduction; TIMP-4; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases - genetics; Tissue Inhibitor of Metalloproteinases - metabolism; tumor progenitor cells; Tumorigenesis; Up-Regulation; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22442

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.