Journal
BRITISH JOURNAL OF CANCER
Volume 122, Issue 3, Pages 421-433Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41416-019-0655-7
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Funding
- EKFS (Else Kroner-Fresenius-Graduiertenkolleg)
- Faculty of Medicine, Goethe-University Frankfurt
- Else Kroner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation-Pharma (TRIP)
- Deutsche Forschungsgemeinschaft [GRK 2336]
- Wilhelm Sander-Stiftung [2017.130.1]
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BACKGROUND: We aimed at clarifying the role of lipocalin-2 (LCN-2) in clear-cell renal cell carcinoma (ccRCC). Since LCN-2 was recently identified as a novel iron transporter, we explored its iron load as a decisive factor in conferring its biological function. METHODS: LCN-2 expression was analysed at the mRNA and protein level by using immunohistochemistry, RNAscope (R) and qRT-PCR in patients diagnosed with clear-cell renal cell carcinoma compared with adjacent healthy tissue. We measured LCN-2-bound iron by atomic absorption spectrometry from patient-derived samples and applied functional assays by using ccRCC cell lines, primary cells, and 3D tumour spheroids to verify the role of the LCN-2 iron load in tumour progression. RESULTS: LCN-2 was associated with poor patient survival and LCN-2 mRNA clustered in high- and low-expressing ccRCC patients. LCN-2 protein was found overexpressed in tumour compared with adjacent healthy tissue, whereby LCN-2 was iron loaded. In vitro, the iron load determines the biological function of LCN-2. Iron-loaded LCN-2 showed pro-tumour functions, whereas iron-free LCN-2 produced adverse effects. CONCLUSIONS: We provide new insights into the pro-tumour function of LCN-2. LCN-2 donates iron to cells to promote migration and matrix adhesion. Since the iron load of LCN-2 determines its pro-tumour characteristics, targeting either its iron load or its receptor interaction might represent new therapeutic options.
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