Linked Life Data

21258414

Source:http://linkedlifedata.com/resource/pubmed/id/21258414

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2011-6-9
pubmed:abstractText
The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-? results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cell-mediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1? and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFN? secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFN?, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFN? resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with anti-angiogenic drugs may be beneficial for patients with mutated VHL.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1476-5594
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2622-32
pubmed:meshHeading
pubmed-meshheading:21258414-Blotting, Western, pubmed-meshheading:21258414-Carcinoma, Renal Cell, pubmed-meshheading:21258414-Cell Hypoxia, pubmed-meshheading:21258414-Cell Line, Tumor, pubmed-meshheading:21258414-Cell Proliferation, pubmed-meshheading:21258414-Cytotoxicity, Immunologic, pubmed-meshheading:21258414-Genetic Complementation Test, pubmed-meshheading:21258414-Histocompatibility Antigens Class I, pubmed-meshheading:21258414-Humans, pubmed-meshheading:21258414-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:21258414-Interferon-alpha, pubmed-meshheading:21258414-Interferon-gamma, pubmed-meshheading:21258414-Kidney Neoplasms, pubmed-meshheading:21258414-Killer Cells, Natural, pubmed-meshheading:21258414-Mutation, pubmed-meshheading:21258414-NK Cell Lectin-Like Receptor Subfamily C, pubmed-meshheading:21258414-RNA Interference, pubmed-meshheading:21258414-Transfection, pubmed-meshheading:21258414-Vascular Endothelial Growth Factor A, pubmed-meshheading:21258414-Von Hippel-Lindau Tumor Suppressor Protein
pubmed:year
2011
pubmed:articleTitle
Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma.
pubmed:affiliation
Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Paris, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't