CAIX-Mediated Control of LIN28/let-7 Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia
| Autor: | Dana Jurkovicova, Kamil Pohlodek, Martina Takacova, Petra Bullova, Hynek Strnad, Eliska Svastova, Silvia Pastorekova, Adriana Gibadulinova |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Homeobox protein NANOG
Pyruvate dehydrogenase kinase Breast Neoplasms medicine.disease_cause Stem cell marker Catalysis Article carbonic anhydrase IX Inorganic Chemistry lcsh:Chemistry Cancer stem cell Antigens Neoplasm Cell Line Tumor medicine Humans Glycolysis Physical and Theoretical Chemistry Molecular Biology lcsh:QH301-705.5 Spectroscopy Chemistry hypoxia Gene Expression Profiling Organic Chemistry RNA-Binding Proteins General Medicine Hydrogen-Ion Concentration Pyruvate dehydrogenase complex Cellular Reprogramming Cell Hypoxia Computer Science Applications MicroRNAs LIN28/let-7 axis lcsh:Biology (General) lcsh:QD1-999 Cancer cell Cancer research MCF-7 Cells Neoplastic Stem Cells Female Carcinogenesis metabolism |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 21, Iss 4299, p 4299 (2020) Volume 21 Issue 12 |
| ISSN: | 1422-0067 |
| Popis: | Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. 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. |
| Databáze: | OpenAIRE |
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