PMID- 23308045
OWN - NLM
STAT- MEDLINE
DCOM- 20130710
LR  - 20220330
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 14
IP  - 12
DP  - 2012 Dec
TI  - Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma 
      metastasis in liver.
PG  - 1122-31
AB  - High circulating cholesterol is associated with hypercholesterolemia, 
      atherosclerosis, and stroke. However, the relation between cholesterol and 
      tumorigenesis/metastasis is controversial. The proprotein convertase 
      subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol 
      homeostasis by targeting the low-density lipoprotein receptor (LDLR) for 
      degradation. PCSK9 is mostly expressed in liver, which is one of the most common 
      sites for metastatic disease. To reveal the function of PCSK9 and also evaluate 
      the impact of cholesterol in liver metastasis development, B16F1 melanoma cells 
      were injected into wild-type (WT) and Pcsk9(-/-) mice to induce liver metastasis. 
      On chow diet, Pcsk9(-/-) mice harbored two-fold less liver metastases than WT 
      mice. This decrease is related to low cholesterol levels in Pcsk9(-/-) mice, as 
      the protection was lost after normalizing Pcsk9(-/-) cholesterol levels by a 
      2-week high cholesterol diet. Furthermore, a prolongation of this diet strongly 
      increased metastasis in both genotypes, suggesting that high cholesterol levels 
      promote metastatic progression. The protective effect of the PCSK9 deficiency is 
      also associated with increased apoptosis in liver stroma and metastases. Tumor 
      necrosis factor.alpha (TNFalpha) mRNA and protein were, respectively, higher in liver 
      stroma and plasma of injected mice, likely increasing the apoptotic TNFalpha 
      signaling. Furthermore, the anti-apoptotic factor B-cell lymphoma 2 was 
      downregulated. TNFalpha regulation is LDLR-independent, as its mRNA level was 
      similarly upregulated in mice lacking both PCSK9 and LDLR. Our findings show that 
      PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol 
      levels and by possibly enhancing TNFalpha-mediated apoptosis.
FAU - Sun, Xiaowei
AU  - Sun X
AD  - Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of 
      Montreal, University of Montreal, Montreal, QC, Canada.
FAU - Essalmani, Rachid
AU  - Essalmani R
FAU - Day, Robert
AU  - Day R
FAU - Khatib, Abdel M
AU  - Khatib AM
FAU - Seidah, Nabil G
AU  - Seidah NG
FAU - Prat, Annik
AU  - Prat A
LA  - eng
GR  - CTP 82946/Canadian Institutes of Health Research/Canada
GR  - MOP 102741/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Cholesterol, Dietary)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, LDL)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 114100-40-2 (Bcl2 protein, mouse)
RN  - EC 3.4.21.- (Pcsk9 protein, mouse)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
RN  - EC 3.4.21.- (Proprotein Convertases)
RN  - EC 3.4.21.- (Serine Endopeptidases)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Adhesion
MH  - Cell Proliferation
MH  - Cholesterol, Dietary/administration & dosage/*adverse effects
MH  - Female
MH  - Gene Expression
MH  - Hep G2 Cells
MH  - Hepatocytes
MH  - Humans
MH  - Liver/*enzymology/metabolism
MH  - Liver Neoplasms/metabolism/*secondary
MH  - Melanoma, Experimental/metabolism/*secondary
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Proprotein Convertase 9
MH  - Proprotein Convertases/*deficiency/genetics/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - RNA, Messenger/metabolism
MH  - Receptors, LDL/metabolism
MH  - Serine Endopeptidases/*deficiency/genetics/metabolism
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
MH  - Up-Regulation
PMC - PMC3540939
EDAT- 2013/01/12 06:00
MHDA- 2013/07/11 06:00
PMCR- 2012/12/01
CRDT- 2013/01/12 06:00
PHST- 2012/07/31 00:00 [received]
PHST- 2012/10/25 00:00 [revised]
PHST- 2012/10/26 00:00 [accepted]
PHST- 2013/01/12 06:00 [entrez]
PHST- 2013/01/12 06:00 [pubmed]
PHST- 2013/07/11 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - 121252 [pii]
AID - 10.1593/neo.121252 [doi]
PST - ppublish
SO  - Neoplasia. 2012 Dec;14(12):1122-31. doi: 10.1593/neo.121252.