Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

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 hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a 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.

Ingår i:Communications biology: Springer Science and Business Media LLC4:1, s. 166-2399-3642

Av författaren/redakt...: Dufies, M; Verbiest, A; Cooley, LS; Ndiaye, PD; He, XK; Nottet, N; visa fler...; Souleyreau, W; Hagege, A; Torrino, S; Parola, J; Giuliano, S; Borchiellini, D; Schiappa, R; Mograbi, B; Zucman-Rossi, J; Bensalah, K; Ravaud, A; Auberger, P; Bikfalvi, A; Chamorey, E; Rioux-Leclercq, ...; Mazure, NM; Beuselinck, B; Cao, YH; Bernhard, JC; Ambrosetti, D; Pages, G; visa färre...

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