| Autor: |
Sandy Giuliano, Nicolas Nottet, Wilfried Souleyreau, Papa Diogop Ndiaye, Damien Ambrosetti, Alain Ravaud, Maeva Dufies, Patrick Auberger, Julien Viotti, Anais Hagege, Emmanuel Chamorey, Stéphanie Torrino, Baharia Mograbi, Annelies Verbiest, Jean-Christophe Bernhard, Xingkang He, Yihai Cao, Jessica Zucman-Rossi, Andreas Bikfalvi, Gilles Pagès, Julien Parola, Nathalie M. Mazure, Benoit Beuselinck, Delphine Borchiellini, Lindsay S. Cooley, Karim Bensalah, Nathalie Rioux-Leclercq, Renaud Schiappa |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
Polo-Like Kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a novel hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a new HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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