Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL

By P. Staller, Jitka Sulitkova, J. Lisztwan, H. Moch, E. Oakeley, W. Krek. Nature, 2003

945 citations recorded by the source corpus.

Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source of the CXCR4-specific ligand stromal cell-derived factor-1α (ref. 1). It is still uncertain how an evolving tumour cell is reprogrammed to express CXCR4, thus implementing the tendency to metastasize to specific organs. Here we show that the von Hippel–Lindau tumour suppressor protein pVHL negatively regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutation of the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival. These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/1cffa70748d63505b7be7cd1ac8912a4ba257e95

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Citations in the corpus

Role of chemokines in tumor growth. (2007, background): “HIF-1-α then induces the expression of CXCR4 [57,58].”
G protein-coupled receptors: novel targets for drug discovery in cancer (2010, background): “and is transcriptionally regulated by hypoxia-inducible factor 1α (HIF1α) stimulation that occurs in the hypoxic tumour microenvironmen”
A ubiquitin ligase complex assembles linear polyubiquitin chains (2006, background): “Kidney cancer cell lines lacking pVHL, a renal cell tumor suppressor gene product which is a substrate recognition subunit of a ubiqui- tin ligase (Kaelin, 2005), have been shown to express HOIL- 1/HOIL-1L mRNA more abundantly than pVHL expressing cells (Staller et al, 2003).”
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Brain metastases: epidemiology and pathophysiology (2005, background): “Another gene activated by hypoxia (CXCR4) is a cytokine receptor that not only stimulates cell migration but also plays a role in enabling tumor cells to home in on specific distant organs [60].”
HIF Transcription Factors, Inflammation, and Immunity (2014, background): “…also known as SDF1a) production by hypoxic tumor cells is driven by HIF-1a (Du et al., 2008; Lin et al., 2012), and chemokine receptor C-X-C motif chemokine receptor (CXCR4) expression by myeloid and tumor cells is regulated by the VHL-HIF axis (Schioppa et al., 2003; Staller et al., 2003).”
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