Induced pluripotent stem cells (iPSCs) have recently boomed enthusiasm in stem cell therapy, whereas high potential tumorigenesis of iPSCs has become the biggest obstacle for clinic application and the tumorigenic genes in iPSCs have not been well documented. In this investigation, using tools of bioinformatics, we analyzed the all available datasets regarded to iPSCs from 11 differentiated cell lines and revealed 593 iPSC consensus genes. Notably, of the 593 genes, 209 were expressed in human tumor cell lines and cancer tissues, and some of them were expressed in the iPSC-differentiated hepatocytes; remarkably, 5 oncogenes were overexpressed in the iPSCs and an oncogene RAB25 in the iPSC-differentiated cells, suggesting that these iPSC consensus genes are implicated with the risk of tumorigenesis and cancers. This investigation provides useful information for designing new strategies and methods to curtail the expression of oncogenic genes in iPSCs and produce safe iPSC derivatives for stem cell therapy.
Get full access to this article
View all access options for this article.
References
1.
TakahashiK, YamanakaS. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126:663–676.
KiskinisE, EgganK. 2010. Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest, 120:51–59.
4.
NelsonTJ, Martinez-FernandezA, YamadaS, Perez-TerzicC, IkedaY, TerzicA. 2009. Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation, 120:408–416.
5.
MoriguchiH, ChungRT, SatoC. 2010. Tumorigenicity of human induced pluripotent stem cells depends on the balance of gene expression between p21 and p53. Hepatology, 51:1088–1089.
6.
GhoshZ, HuangM, HuS, WilsonKD, DeyD, WuJC. 2011. Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res, 71:5030–5039.
7.
WuSM, HochedlingerK. 2011. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol, 13:497–505.
8.
PlathK, LowryWE. 2011. Progress in understanding reprogramming to the induced pluripotent state. Nat Rev Genet, 12:253–265.
9.
PappB, PlathK. 2011. Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res, 21:486–501.
10.
NewmanAM, CooperJB. 2010. AutoSOME: a clustering method for identifying gene expression modules without prior knowledge of cluster number. BMC Bioinformatics, 11:117.
11.
WangY, MahN, PrigioneA, WolfrumK, Andrade-NavarroMA, AdjayeJ. 2010. A transcriptional roadmap to the induction of pluripotency in somatic cells. Stem Cell Rev, 6:282–296.
12.
JosephP, MuchnokTK, KlishisML, RobertsJR, AntoniniJM, WhongWZ, OngT. 2001. Cadmium-induced cell transformation and tumorigenesis are associated with transcriptional activation of c-fos, c-jun, and c-myc proto-oncogenes: role of cellular calcium and reactive oxygen species. Toxicol Sci, 61:295–303.
13.
LinSL, ChangDC, YingSY, LeuD, WuDT. 2010. MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways. Cancer Res, 70:9473–9482.
14.
AshburnerM, BallCA, BlakeJA, BotsteinD, ButlerH, CherryJM, DavisAP, DolinskiK, DwightSSet al.2000. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet, 25:25–29.
15.
HuangDW, ShermanBT, LempickiRA. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc, 4:44–57.
16.
von MeringC, JensenLJ, SnelB, HooperSD, KruppM, FoglieriniM, JouffreN, HuynenMA, BorkP. 2005. STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res, 33:D433–D437.
17.
NishinoK, ToyodaM, Yamazaki-InoueM, FukawataseY, ChikazawaE, SakaguchiH, AkutsuH, UmezawaA. 2011. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet, 7:e1002085.
18.
DengJ, ShoemakerR, XieB, GoreA, LeProustEM, Antosiewicz-BourgetJ, EgliD, MaheraliN, ParkIHet al.2009. Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol, 27:353–360.
19.
LiZ, YangCS, NakashimaK, RanaTM. 2011. Small RNA-mediated regulation of iPS cell generation. Embo J, 30:823–834.
20.
ChanSW, HendersonIR, JacobsenSE. 2005. Gardening the genome: DNA methylation in Arabidopsis thaliana. Nat Rev Genet, 6:351–360.
21.
ChenH, Shalom-FeuersteinR, RileyJ, ZhangSD, TucciP, AgostiniM, AberdamD, KnightRA, GenchiGet al.2010. miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro. Biochem Biophys Res Commun, 394:921–927.
22.
RosaA, SpagnoliFM, BrivanlouAH. 2009. The miR-430/427/302 family controls mesendodermal fate specification via species-specific target selection. Dev Cell, 16:517–527.
23.
StadlerB, IvanovskaI, MehtaK, SongS, NelsonA, TanY, MathieuJ, DarbyC, BlauCAet al.2010. Characterization of microRNAs involved in embryonic stem cell states. Stem Cells Dev, 19:935–950.
24.
Barroso-delJA, Lucena-AguilarG, MenendezP. 2009. The miR-302–367 cluster as a potential stemness regulator in ESCs. Cell Cycle, 8:394–398.
25.
YuJ, WangF, YangGH, WangFL, MaYN, DuZW, ZhangJW. 2006. Human microRNA clusters: genomic organization and expression profile in leukemia cell lines. Biochem Biophys Res Commun, 349:59–68.
26.
LinSL, ChangDC, Chang-LinS, LinCH, WuDT, ChenDT, YingSY. 2008. Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA, 14:2115–2124.
27.
ParkJ, KimC, TangY, AmanoT, LinCJ, TianXC. 2011. Reprogramming of mouse fibroblasts to an intermediate state of differentiation by chemical induction. Cell Reprogram, 13:121–131.
28.
ChenG, GulbransonDR, HouZ, BolinJM, RuottiV, ProbascoMD, Smuga-OttoK, HowdenSE, DiolNRet al.2011. Chemically defined conditions for human iPSC derivation and culture. Nat Methods, 8:424–429.
29.
MiyoshiN, IshiiH, NaganoH, HaraguchiN, DewiDL, KanoY, NishikawaS, TanemuraM, MimoriKet al.2011. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell, 8:633–638.
30.
SubramanyamD, LamouilleS, JudsonRL, LiuJY, BucayN, DerynckR, BlellochR. 2011. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol, 29:443–448.
31.
Anokye-DansoF, TrivediCM, JuhrD, GuptaM, CuiZ, TianY, ZhangY, YangW, GruberPJ, EpsteinJA, MorriseyEE. 2011. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8:376–388.
32.
ChambersSM, StuderL. 2011. Cell fate plug and play: direct reprogramming and induced pluripotency. Cell, 145:827–830.
33.
WarrenL, ManosPD, AhfeldtT, LohYH, LiH, LauF, EbinaW, MandalPK, SmithZDet al.2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7:618–630.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
