2010/2/28
Evid
Based Complement Alternat Med. 2009 Aug 20. [Epub ahead of print] Hsu JW, Huang HC, Chen ST, Wong CH, Juan HF. Department of Life Science,
Institute of Molecular and Cellular Biology, National Taiwan University, No
1, Sec. 4, Roosevelt Road, Taipei, 106 Taiwan. yukijuan@ntu.edu.tw,
yukijuan@gmail.com. Differentiation therapy by
induction of tumor cells is an important method in the treatment of hematological
cancers such as leukemia. Tumor cell differentiation ends cancer cells'
immortality, thus stopping cell growth and proliferation. In our previous
study, we found that fucose-containing polysaccharide fraction F3 extracted
from Ganoderma lucidum can bring about cytokine secretion and cell death in
human leukemia THP-1 cells. This prompted us to further investigate on how
F3 induces the differentiation in human leukemia cells. We integrated
time-course microarray analysis and network modeling to study the
F3-induced effects on THP-1 cells. In addition, we determined the
differentiation effect using Liu's staining, nitroblue tetrazolium (NBT)
reduction assay, flow cytometer, western blotting and Q-PCR. We also
examined the modulation and regulation by F3 during the differentiation
process. Dynamic gene expression profiles showed that cell differentiation
was induced in F3-treated THP-1 cells. Furthermore, F3-treated THP-1 cells
exhibited enhanced macrophage differentiation, as demonstrated by changes
in cell adherence, cell cycle arrest, NBT reduction and expression of
differentiation markers including CD11b, CD14, CD68, matrix
metalloproteinase-9 and myeloperoxidase. In addition, caspase cleavage and
p53 activation were found to be significantly enhanced in F3-treated THP-1
cells. We unraveled the role of caspases and p53 in F3-induced THP-1 cells
differentiation into macrophages. Our results provide a molecular
explanation for the differentiation effect of F3 on human leukemia THP-1
cells and offer a prospect for a potential leukemia differentiation
therapy. PMID: 19696196 [PubMed - as
supplied by publisher Clin Chem.2009 Oct;55(10):1834-42. Epub 2009 Aug 6. Regina
S,Valentin JB,Lachot S,LemariéE,Rollin J,Gruel Y. Department
ofHematology-Hemostasis, Trousseau Hospital and François Rabelais
University,Tours, France. BACKGROUND: Tissue
factor(TF), the main initiator of blood coagulation, is also a signaling
proteinthat regulates cancer progression. TF synthesis was recently shown
to beaffected by tumor suppressor genes (TSGs) in tumor cell lines. We
thereforestudied TF gene (F3) expression and the status of genes coding for
tumorprotein p53 (TP53), phosphatase and tensin homolog (PTEN),
andserine/threonine kinase 11 (STK11) in non-small cell lung cancer
(NSCLC).Heparanase (HPSE) gene expression was also measured because
thisendo-beta-D-glucuronidase was recently shown to enhance TF gene
expression.METHODS: TF and heparanase mRNA expression was measured by
real-time PCR in53 NSCLC tumors. Exons 5-8 of TP53 were sequenced from
genomic DNA.Mutations of PTEN and STK11 were screened by multiplex
ligation-dependentprobe amplification. RESULTS: TF mRNA levels were
significantly higher inT(3)-T(4) tumors (P = 0.04) and in stages III-IV of
NSCLC (P = 0.03).Mutations of TP53, STK11, and PTEN were identified in 20
(37.7%), 21 (39%),and 20 (37.7%) of tumors, respectively. TF expression was
higher in mutatedTP53 (TP53(Mut)) (P = 0.02) and PTEN(Mut) (P = 0.03)
samples. Moreover, TFmRNA increased from 2700 copies (no mutation) to 11
6415 when 3 TSG weremutated. Heparanase gene expression did not differ
according to TF gene(F3) expression or TSG mutation. The median survival
time was shorter inpatients with tumor TF mRNA levels above median values
(relative risk 2.2;P = 0.03, multivariate analysis) and when TP53 was
mutated (relative risk1.8; P = 0.02). CONCLUSIONS: These results provide
clear evidence thatcombined oncogene events affecting TSG dramatically
increase TF geneexpression in lung tumors. Moreover, this study suggests
that TF geneexpression could be used as a prognostic marker in NSCLC. PMID: 19661141 [PubMed J Biol Chem. 2006 Aug
25;281(34):24111-23. Epub 2006 Jun 23. Lin KI, Kao YY, Kuo HK, Yang WB, Chou A, Lin HH, Yu AL, Wong CH. Genomics Research Center,
Academia Sinica, Taipei 115, Taiwan. kuoilin@gate.sinca.edu.tw The polysaccharides of
Ganoderma lucidum (Reishi) possess immunomodulation activities; however,
their mode of molecular action in regulating each cellular subset in the
immune system is still not clear. Here, we investigate the function of the
main polysaccharide fraction of Reishi (Reishi-F3) in B lymphocyte
activation/differentiation. We find that Reishi-F3 causes mouse splenic B
cell activation and differentiation to IgM-secreting plasma cells, and the
process depends on Reishi-F3-mediated induction of Blimp-1, a master
regulator capable of triggering the changes of a cascade of gene expression
during plasmacytic differentiation. In human peripheral B lymphocytes,
although Reishi-F3 fails to induce their activation, it is able to enhance
antibody secretion, which is associated with Blimp-1 mRNA induction. The
function of Reishi-F3 depends on the Toll-like receptors TLR4/TLR2 as
neutralizing antibodies against TLR4/TLR2 block Reishi-F3-mediated
induction of Blimp-1 mRNA and Ig secretion. We have shown that interaction
of Reishi-F3 with TLR4/TLR2 followed by signaling through p38 MAPK is
involved in the induction of Blimp-1 mRNA, whereas signaling through ERK,
p38 MAPK, JNK, and IKK complex is involved in Reishi-F3-mediated Ig
secretion. Furthermore, the differential mechanism of Reishi-F3 in mouse
and human B cell activation is probably due to the presence of Blimp-1
regulatory site in human CD86 promoter. These results establish the
signaling and molecular mechanisms of Reishi-F3 on promoting antibody secretion. PMID: 16798741 [PubMed -
indexed for
Ganoderma lucidum
Polysaccharides Induce Macrophage-like Differentiation in Human Leukemia
THP-1 Cells via Caspase and p53 Activation.
Increased tissue
factorexpression is associated with reduced survival in non-small cell
lungcancer and with mutations of TP53 and PTEN.
Reishi polysaccharides
induce immunoglobulin production through the TLR4/TLR2-mediated induction
of transcription factor Blimp-1.
.