{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:40:36Z","timestamp":1789569636700,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,11,30]],"date-time":"2015-11-30T00:00:00Z","timestamp":1448841600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"CONACyT","award":["132931"],"award-info":[{"award-number":["132931"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:label\/><jats:p>Tissue inhibitor of metalloproteinase\u20104 (TIMP\u20104) belongs to a family of extracellular matrix (ECM) metalloproteinases inhibitors that are overexpressed in several cancers. However, the role of TIMP\u20104 during carcinogenesis is poorly understood. To evaluate TIMP\u20104 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\u20104 molecular mechanisms. In the present report, we show that in nude mice, cervical cancer cells that overexpress TIMP\u20104 formed tumors faster than control cell\u2010derived tumors. Furthermore, in vivo limiting dilution assays showed that fewer TIMP\u20104 overexpressing cells are needed for tumor formation. In vitro analyses demonstrated that TIMP\u20104 overexpression or exposure to human recombinant TIMP\u20104 (hrTIMP4) caused an enrichment of the tumor progenitor cell (TPC) population. Accordingly, genome\u2010wide expression and signaling pathway analyses showed that hrTIMP\u20104 modulated cell survival, cell proliferation, inflammation, and epithelial\u2010mesenchymal transition (EMT) signaling networks. Notably, NF\u03baB signaling pathway appeared to be globally activated upon hrTIMP\u20104 treatment. Overall, this report provides the first example that TIMP\u20104 regulates carcinogenesis through enriching the TPC population in cervical cancer cells. Understanding TIMP\u20104 effects on tumorigenesis may provide clues for future therapies design. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mc.22442","type":"journal-article","created":{"date-parts":[[2015,11,30]],"date-time":"2015-11-30T15:58:38Z","timestamp":1448899118000},"page":"1952-1961","source":"Crossref","is-referenced-by-count":31,"title":["Tissue inhibitor of metalloproteinases\u20104 (TIMP\u20104) regulates stemness in cervical cancer cells"],"prefix":"10.1002","volume":"55","author":[{"given":"Floria","family":"Lizarraga","sequence":"first","affiliation":[{"name":"Epigenetics Laboratory, Medical Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Functional Genomics Laboratory, Basic Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela","family":"Ceballos\u2010Cancino","sequence":"additional","affiliation":[{"name":"Functional Genomics Laboratory, Basic Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Vazquez\u2010Santillan","sequence":"additional","affiliation":[{"name":"Epigenetics Laboratory, Medical Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Bahena\u2010Ocampo","sequence":"additional","affiliation":[{"name":"Functional Genomics Laboratory, Basic Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Schwarz\u2010Cruz y Celis","sequence":"additional","affiliation":[{"name":"Functional Genomics Laboratory, Basic Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Vega\u2010Gordillo","sequence":"additional","affiliation":[{"name":"Functional Genomics Laboratory, Basic Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Garcia Lopez","sequence":"additional","affiliation":[{"name":"Pharmacology Laboratory, Basic Research Subdirection National Institute of Cancerology Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilma","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Epigenetics Laboratory, Medical Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Melendez\u2010Zajgla","sequence":"additional","affiliation":[{"name":"Functional Genomics Laboratory, Basic Research Subdirection National Institute of Genomic Medicine Ciudad de M\u00e9xico Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,11,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-7-85"},{"key":"e_1_2_7_3_1","first-page":"2365","article-title":"Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery","volume":"61","author":"Jiang Y","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-8258(03)00077-5"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.1854"},{"key":"e_1_2_7_6_1","first-page":"623","article-title":"Tissue inhibitor of metalloproteinases\u20104 is expressed in cervical cancer patients","volume":"25","author":"Lizarraga F","year":"2005","journal-title":"Anticancer Res"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.03.027"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3599"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.3.12.1280"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.74"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706728104"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-008-0378-3"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2009.06.008"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(97)00150-4"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2014.05.002"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:DDAS.0000043375.35611.dd"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-011-1725-6"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.23.6627"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.2000.5118"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601281"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210560"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63624-3"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.5.1047"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.02.004"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-006-7893-x"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2881"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205291"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204508"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-010713-141310"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800956"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmc.22442","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmc.22442","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.22442","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T20:22:29Z","timestamp":1694982149000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.22442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,30]]},"references-count":30,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1002\/mc.22442"],"URL":"https:\/\/doi.org\/10.1002\/mc.22442","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,30]]}}}