PMID- 20099300
OWN - NLM
STAT- MEDLINE
DCOM- 20100421
LR  - 20220321
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 51
IP  - 4
DP  - 2010 Apr
TI  - Sorafenib inhibits the shedding of major histocompatibility complex class 
      I-related chain A on hepatocellular carcinoma cells by down-regulating a 
      disintegrin and metalloproteinase 9.
PG  - 1264-73
LID - 10.1002/hep.23456 [doi]
AB  - The ectodomain of major histocompatibility complex class I-related chain A (MICA) 
      is shed from tumor cells, and may be an important means of evading antitumor 
      immunity. This study investigated the roles of a disintegrin and 
      metalloproteinase 9 (ADAM9) in the shedding of MICA in human hepatocellular 
      carcinoma (HCC). Small interfering RNA-mediated knockdown (KD) of ADAM9 resulted 
      in up-regulation of membrane-bound MICA expression on the HepG2 and PLC/PRF/5 
      cellular surfaces and down-regulation of soluble MICA levels in their culture 
      supernatant. ADAM9 was cleaved at a site between Gln347 and Val348 of MICA in 
      vitro. We constructed a plasmid of the MICA gene with mutation or deletion of the 
      ADAM9 cleavage site to examine the detailed mechanism of MICA shedding by ADAM9 
      protease. The results suggested that MICA might be cleaved at the intracellular 
      ADAM9-recognized cleavage site and was further cleaved at the extracellular 
      ADAM9-independent cleavage site in HCC cells, resulting in the production of 
      soluble MICA. Immunohistochemical analysis revealed that ADAM9 was overexpressed 
      in human HCC compared to normal liver tissues. The cytolytic activity of natural 
      killer (NK) cells against ADAM9KD-HCC cells was higher than that against control 
      cells, and the enhancement of this cytotoxicity depended on the MICA/B and NK 
      group 2, member D pathway. Sorafenib treatment resulted in decreased expression 
      of ADAM9, increased expression of membrane-bound MICA expression, and decreased 
      levels of soluble MICA in HCC cells. Adding sorafenib enhanced the NK sensitivity 
      of HCC cells via increased expression of membrane-bound MICA. CONCLUSION: ADAM9 
      is involved in MICA ectodomain shedding in HCC cells, and sorafenib can modulate 
      ADAM9 expression. Sorafenib therapy may have a previously unrecognized effect on 
      antitumor immunity in patients with HCC.
FAU - Kohga, Keisuke
AU  - Kohga K
AD  - Department of Gastroenterology and Hepatology, Osaka University Graduate School 
      of Medicine, Osaka, Japan.
FAU - Takehara, Tetsuo
AU  - Takehara T
FAU - Tatsumi, Tomohide
AU  - Tatsumi T
FAU - Ishida, Hisashi
AU  - Ishida H
FAU - Miyagi, Takuya
AU  - Miyagi T
FAU - Hosui, Atsushi
AU  - Hosui A
FAU - Hayashi, Norio
AU  - Hayashi N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Benzenesulfonates)
RN  - 0 (Dipeptides)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (MHC class I-related chain A)
RN  - 0 (Membrane Proteins)
RN  - 0 
      (N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 
      2-aminoethylamide)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (ADAM9 protein, human)
SB  - IM
MH  - ADAM Proteins/antagonists & inhibitors/*physiology
MH  - Benzenesulfonates/*pharmacology
MH  - Carcinoma, Hepatocellular/*drug therapy
MH  - Cell Line, Tumor
MH  - Dipeptides/pharmacology
MH  - Down-Regulation
MH  - Histocompatibility Antigens Class I/analysis/chemistry/*physiology
MH  - Humans
MH  - Hydroxamic Acids/pharmacology
MH  - Killer Cells, Natural/immunology
MH  - Liver Neoplasms/*drug therapy
MH  - Membrane Proteins/antagonists & inhibitors/*physiology
MH  - Niacinamide/analogs & derivatives
MH  - Phenylurea Compounds
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyridines/*pharmacology
MH  - Sorafenib
EDAT- 2010/01/26 06:00
MHDA- 2010/04/22 06:00
CRDT- 2010/01/26 06:00
PHST- 2010/01/26 06:00 [entrez]
PHST- 2010/01/26 06:00 [pubmed]
PHST- 2010/04/22 06:00 [medline]
AID - 10.1002/hep.23456 [doi]
PST - ppublish
SO  - Hepatology. 2010 Apr;51(4):1264-73. doi: 10.1002/hep.23456.