PMID- 21258414
OWN - NLM
STAT- MEDLINE
DCOM- 20110819
LR  - 20201219
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 30
IP  - 23
DP  - 2011 Jun 9
TI  - Mutations of the von Hippel-Lindau gene confer increased susceptibility to 
      natural killer cells of clear-cell renal cell carcinoma.
PG  - 2622-32
LID - 10.1038/onc.2010.638 [doi]
AB  - 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)-alpha 
      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)-1alpha 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 IFNgamma 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 IFNalpha, the exponential growth of RCC-pVHL was inhibited more than that 
      of RCC-pE cells, indicating that VHL mutations may be involved in IFNalpha 
      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.
FAU - Perier, A
AU  - Perier A
AD  - Institut Cochin, INSERM U1016, CNRS UMR 8104, Universite Paris Descartes, Paris, 
      France.
FAU - Fregni, G
AU  - Fregni G
FAU - Wittnebel, S
AU  - Wittnebel S
FAU - Gad, S
AU  - Gad S
FAU - Allard, M
AU  - Allard M
FAU - Gervois, N
AU  - Gervois N
FAU - Escudier, B
AU  - Escudier B
FAU - Azzarone, B
AU  - Azzarone B
FAU - Caignard, A
AU  - Caignard A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110124
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (HIF1A protein, human)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Interferon-alpha)
RN  - 0 (NK Cell Lectin-Like Receptor Subfamily C)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
SB  - IM
MH  - Blotting, Western
MH  - Carcinoma, Renal Cell/genetics/immunology/pathology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cytotoxicity, Immunologic/*genetics/immunology
MH  - Genetic Complementation Test
MH  - Histocompatibility Antigens Class I/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/immunology/metabolism
MH  - Interferon-alpha/pharmacology
MH  - Interferon-gamma/immunology/metabolism
MH  - Kidney Neoplasms/genetics/immunology/pathology
MH  - Killer Cells, Natural/immunology/*metabolism
MH  - *Mutation
MH  - NK Cell Lectin-Like Receptor Subfamily C/metabolism
MH  - RNA Interference
MH  - Transfection
MH  - Vascular Endothelial Growth Factor A/immunology/metabolism
MH  - Von Hippel-Lindau Tumor Suppressor Protein/*genetics/metabolism
EDAT- 2011/01/25 06:00
MHDA- 2011/08/20 06:00
CRDT- 2011/01/25 06:00
PHST- 2011/01/25 06:00 [entrez]
PHST- 2011/01/25 06:00 [pubmed]
PHST- 2011/08/20 06:00 [medline]
AID - onc2010638 [pii]
AID - 10.1038/onc.2010.638 [doi]
PST - ppublish
SO  - Oncogene. 2011 Jun 9;30(23):2622-32. doi: 10.1038/onc.2010.638. Epub 2011 Jan 24.