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SFRP1 is a possible candidate for epigenetic therapy in nonsmall cell lung cancer
Yh. Taguchi1, Mitsuo Iwadate2,
Hideaki Umeyama2
Department of Physics1/Biological Science2, Chuo University
Presentation at TBC2015BMC Med. Geno. Supp. in press
Non small cell lung cancer (NSCLC) was lethal cancer, whose five year survival rate is at most less than 50%.Recently, epigenetic therapy that target epigenetic regulation of genes raised as a new therapy strategy for NSCLC
In contrast to the many in vivo studies, there exists a relatively small number of in vitro studies.
The reason why there are small number of studies is because in vitro treatment of NSCLC is often failed to be reproduced.
The lack of in vitro study keep us from identifying target genes of epigenetic therapy
Instead of direct investigation of in vitro effect of epigenetic therapy, we considered reprogrammed NSCLC cell line where epigenetic profiles is expected to be altered.
Samples (GSE35913)
H1 (ES cell), H358 and H460 (NSCLC),IMR90
(Human Caucasian fetal lung fibroblast), iPCH358, iPCH460, iPSIMR90
(reprogrammed cell lines),piPCH358 (redifferentiated iPCH358)
With three biological replicates. 3 x 8 = 24 samples
for gene expression/promoter methylation
Our strategyOur strategy
Gene expression
Promoter methylation
FE
FE
Top 300 significant genes
Top 300 significant genes
Genes selected commonly in both FE
What is PCA based unsupervised FE?
N features
Categorical multiclasses
In contrast to usual usage of PCA, not samples but features are embedded into Q dimensional space.
PC
A
PC1
samplesPC Loadings
M samplesN × M Matrix X (numerical values)
PC2
PC1
PC Score
++ ++ +
+++
++ ++ ++
+
No distinction between classes
Synthetic example
10 samples10 samples
90 features 10 featuresN(0)N()
[N()+N(0)]/2
+:Top 10 outliersThus, extracting outliers selects features distinct between two classes in an unsupervised way.Accuracy:(100 trials)Accuracy:(100 trials) 89.5% ( 52.6% (
PC1
PC2
Normal μ:mean Distribution ½ :SD
Categorical regression based FEG
ene
expr
essi
onP
rom
oter
met
hyla
tion
Category
Features more coincident with multple categories are selected
To identify PC loadings used for FE, we applied hierarchical clustering of PC loadings
Gene expression
Promotermethylation
PC3 vs PC3
PC4 vs PC4
(A) Associations with cancer related genes reported by Gendoo server. (B) Significant negative correlations (P<0.05) between gene expression and promoter methylation. (C) At least one study reported a direct/indirect relationship withNSCLC. (D) At least one study reported a direct/indirect relationship with Wnt/ catenin signalling pathways.β
Comparison of gene expression between resistant and nonresistant cell lines for adenocarcinoma and squamous cell carcinoma
Potential of SFRP1 binding to WNT1
(a)WNT1 + SFRP1 by Fiberdock + ZDOCK, (b)WNT8 + CRD of FZ8 by Fiberdock + ZDOCK,(c) WNT1 + SFRP1 (by GROMACS (time = 2 ns)(d) WNT8 + CRD of Fz8 in PDB (PDB ID: 4F0A)
ConclusionConclusion
We identify multiple genes associated with aberrant gene expression and promoter methylation during NSCLC reprogramming
Wnt/ catenin signalling pathways is critical βtarget of NSCLC therapy
SFRP1 is supposed to be epigenetic theraphy target and it binding affinity to Wnt1 was investigated.