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Nowicka, A.M.* ; Häuselmann, I.* ; Borsig, L.* ; Bolduan, S. ; Schindler, M. ; Schraml, P.* ; Heikenwälder, M. ; Moch, H.*

A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization.

Oncogene 35, 3125-3138 (2016)
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Activation of hypoxia-inducible factor (HIF) is due to loss of von Hippel-Lindau protein (pVHL) function in most clear cell renal cell carcinomas (ccRCCs). Here we describe a novel pVHL-independent mechanism of HIF regulation and identify nuclear factor (NF)-κB essential modulator (NEMO) as a hitherto unknown oncogenic factor influencing human ccRCC progression. Over 60% of human ccRCCs (n=157) have negative or weak NEMO protein expression by immunohistochemistry. Moderate/strong NEMO protein expression is more frequent in VHL wild-type ccRCCs. We show that NEMO stabilizes HIFα via direct interaction and independently of NF-κB signaling in vitro. NEMO prolongs tumor cell survival via regulation of apoptosis and activation of epithelial-to-mesenchymal transition, facilitating tumor metastasis. Our findings suggest that NEMO-driven HIF activation is involved in progression of ccRCC. Therefore, NEMO may represent a clinically relevant link between NF-κB and the VHL/HIF pathways. Targeting NEMO with specific inhibitors in patients with metastatic ccRCC could be a novel treatment approach in patients with ccRCC expressing functional pVHL.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nf-kappa-b; Lindau Tumor-suppressor; Cell Carcinoma-cells; Hepatocellular-carcinoma; Ikk Complex; Regulatory Subunit; Genotoxic Stimuli; Prognostic Value; Kinase Complex; Cyst Formation
ISSN (print) / ISBN 0950-9232
e-ISSN 0950-9232
Zeitschrift Oncogene
Quellenangaben Band: 35, Heft: 24, Seiten: 3125-3138 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed