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Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects of CA9-silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels of let-7 (lethal-7) family members. Simultaneously with the increase of let-7 miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28\/let-7 axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis.<\/jats:p>","DOI":"10.3390\/ijms21124299","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T13:20:43Z","timestamp":1592313643000},"page":"4299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["CAIX-Mediated Control of LIN28\/let-7 Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia"],"prefix":"10.3390","volume":"21","author":[{"given":"Adriana","family":"Gibadulinova","sequence":"first","affiliation":[{"name":"Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Bullova","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hynek","family":"Strnad","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics, The Czech Academy of Sciences, V\u00edde\u0148sk\u00e1 1083, 142 20 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2765-3680","authenticated-orcid":false,"given":"Kamil","family":"Pohlodek","sequence":"additional","affiliation":[{"name":"2nd Department of Gynecology and Obstetrics, Faculty of Medicine, Comenius University of Bratislava, Ruzinovska 6, 821 01 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7997-6932","authenticated-orcid":false,"given":"Dana","family":"Jurkovicova","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Takacova","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Pastorekova","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliska","family":"Svastova","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.semcancer.2014.08.002","article-title":"Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use","volume":"31","author":"Pastorek","year":"2015","journal-title":"Semin. 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