Home LiteratureArticle Details
PMID: 20203285 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Function of EWS-POU5F1 in sarcomagenesis and tumor cell maintenance.

The American journal of pathology ·Vol. 176 ·No. 4 ·2010-04-00 ·Pages 1973-82

Fujino T, Nomura K, Ishikawa Y, Makino H, Umezawa A, Aburatani H, Nagasaki K, Nakamura T

Abstract

POU5F1 is a transcription factor essential for the self-renewal activity and pluripotency of embryonic stem cells and germ cells. We have previously reported that POU5F1 is fused to EWSR1 in a case of undifferentiated sarcoma with chromosomal translocation t(6;22)(p21;q12). In addition, the EWS-POU5F1 chimeras have been recently identified in human neoplasms of the skin and salivary glands. To clarify the roles of the EWS-POU5F1 chimera in tumorigenesis and tumor cell maintenance, we used small-interfering RNA-mediated gene silencing. Knockdown of EWS-POU5F1 in the t(6;22) sarcoma-derived GBS6 cell line resulted in a significant decrease of cell proliferation because of G1 cell cycle arrest associated with p27(Kip1) up-regulation. Moreover, senescence-like morphological changes accompanied by actin polymerization were observed. In contrast, EWS-POU5F1 down-regulation markedly increased the cell migration and invasion as well as activation of metalloproteinase 2 and metalloproteinase 14. The results indicate that the proliferative activity of cancer cells and cell motility are discrete processes in multistep carcinogenesis. These findings reveal the functional role of the sarcoma-related chimeric protein as well as POU5F1 in the development and progression of human neoplasms.

MeSH Terms
Cell Line, Tumor Cell Movement Cellular Senescence Cyclin-Dependent Kinase Inhibitor p27 Flow Cytometry/methods Humans Intracellular Signaling Peptides and Proteins/metabolism Neoplasm Invasiveness Octamer Transcription Factor-3/biosynthesis,genetics Oligonucleotide Array Sequence Analysis RNA Interference RNA, Small Interfering/metabolism RNA-Binding Protein EWS/biosynthesis,genetics Sarcoma/metabolism,pathology Skin Neoplasms/pathology
Chemicals
CDKN1B protein, human Intracellular Signaling Peptides and Proteins Octamer Transcription Factor-3 POU5F1 protein, human RNA, Small Interfering RNA-Binding Protein EWS Cyclin-Dependent Kinase Inhibitor p27
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Fujino Takashi
Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Nomura Kimie
Ishikawa Yuichi
Makino Hatsune
Umezawa Akihiro
Aburatani Hiroyuki
Nagasaki Koichi
Nakamura Takuro
References (42)
42 references, click to expand
  1. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.
    Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14133-8 PMID: 14617776
  2. LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells.
    Cardiovasc Res. 2009 Oct 1;84(1):127-36 PMID: 19487339
  3. A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer.
    Oncogene. 2004 Feb 26;23(8):1636-44 PMID: 14716297
  4. p27Kip1 modulates cell migration through the regulation of RhoA activation.
    Genes Dev. 2004 Apr 15;18(8):862-76 PMID: 15078817
  5. Human embryonic stem cells express a unique set of microRNAs.
    Dev Biol. 2004 Jun 15;270(2):488-98 PMID: 15183728
  6. Oct-4: a germline-specific transcription factor mapping to the mouse t-complex.
    EMBO J. 1990 Jul;9(7):2185-95 PMID: 2357966
  7. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors.
    Cell. 1992 Aug 7;70(3):389-99 PMID: 1643657
  8. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.
    Science. 1995 Jun 2;268(5215):1336-8 PMID: 7761852
  9. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.
    Cell. 1998 Oct 30;95(3):379-91 PMID: 9814708
  10. Examination of POU homeobox gene expression in human breast cancer cells.
    Int J Cancer. 1999 Mar 31;81(1):104-12 PMID: 10077160
  11. CDK inhibitors: positive and negative regulators of G1-phase progression.
    Genes Dev. 1999 Jun 15;13(12):1501-12 PMID: 10385618
  12. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.
    Cell. 2005 Feb 11;120(3):303-13 PMID: 15707890
  13. EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12).
    Genes Chromosomes Cancer. 2005 Jun;43(2):217-22 PMID: 15729702
  14. Core transcriptional regulatory circuitry in human embryonic stem cells.
    Cell. 2005 Sep 23;122(6):947-56 PMID: 16153702
  15. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells.
    Nat Genet. 2006 Apr;38(4):431-40 PMID: 16518401
  16. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.
    Hum Mol Genet. 2006 Jul 1;15(13):2125-37 PMID: 16717057
  17. Dissecting self-renewal in stem cells with RNA interference.
    Nature. 2006 Aug 3;442(7102):533-8 PMID: 16767105
  18. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
    Cell. 2006 Aug 25;126(4):663-76 PMID: 16904174
  19. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.
    Genes Dev. 2006 Dec 15;20(24):3426-39 PMID: 17182868
  20. The hallmarks of cancer.
    Cell. 2000 Jan 7;100(1):57-70 PMID: 10647931
  21. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.
    Nat Genet. 2000 Apr;24(4):372-6 PMID: 10742100
  22. Genes involved in senescence and immortalization.
    Curr Opin Cell Biol. 2000 Dec;12(6):705-9 PMID: 11063935
  23. Interaction of IGF-binding protein-related protein 1 with a novel protein, neuroendocrine differentiation factor, results in neuroendocrine differentiation of prostate cancer cells.
    J Clin Endocrinol Metab. 2001 Sep;86(9):4504-11 PMID: 11549700
  24. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.
    Cell. 2001 Oct 5;107(1):27-41 PMID: 11595183
  25. Identification of tissue-specific microRNAs from mouse.
    Curr Biol. 2002 Apr 30;12(9):735-9 PMID: 12007417
  26. The cell surface: the stage for matrix metalloproteinase regulation of migration.
    Curr Opin Cell Biol. 2002 Oct;14(5):624-32 PMID: 12231359
  27. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors.
    Cancer Res. 2003 May 1;63(9):2244-50 PMID: 12727846
  28. Role of pericellular proteolysis by membrane-type 1 matrix metalloproteinase in cancer invasion and angiogenesis.
    Cancer Metastasis Rev. 2003 Jun-Sep;22(2-3):129-43 PMID: 12784992
  29. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.
    Cell. 2003 Jun 13;113(6):703-16 PMID: 12809602
  30. The small RNA profile during Drosophila melanogaster development.
    Dev Cell. 2003 Aug;5(2):337-50 PMID: 12919683
  31. Membrane-type 1 matrix metalloproteinase and cell migration.
    Biochem Soc Symp. 2003;(70):253-62 PMID: 14587298
  32. Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling.
    PLoS One. 2006;1:e26 PMID: 17183653
  33. OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer.
    Int J Cancer. 2007 Apr 1;120(7):1598-602 PMID: 17205510
  34. Regulation of the actin cytoskeleton in cancer cell migration and invasion.
    Biochim Biophys Acta. 2007 May;1773(5):642-52 PMID: 16926057
  35. The EWS-Oct-4 fusion gene encodes a transforming gene.
    Biochem J. 2007 Sep 15;406(3):519-26 PMID: 17564582
  36. POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands.
    J Pathol. 2008 May;215(1):78-86 PMID: 18338330
  37. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors.
    Nature. 2008 Jul 31;454(7204):646-50 PMID: 18594515
  38. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells.
    Mol Cell Biol. 2008 Oct;28(20):6426-38 PMID: 18710938
  39. Embryonic stem cell-specific miR302-367 cluster: human gene structure and functional characterization of its core promoter.
    Mol Cell Biol. 2008 Nov;28(21):6609-19 PMID: 18725401
  40. Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion.
    J Biol Chem. 2008 Nov 7;283(45):30549-56 PMID: 18757369
  41. Caveolin-1 (P132L), a common breast cancer mutation, confers mammary cell invasiveness and defines a novel stem cell/metastasis-associated gene signature.
    Am J Pathol. 2009 May;174(5):1650-62 PMID: 19395651
  42. Oct-3/4 is a dose-dependent oncogenic fate determinant.
    Cancer Cell. 2003 Nov;4(5):361-70 PMID: 14667503
Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
1525-2191
DOI
10.2353/ajpath.2010.090486
Published
2010-04-00
Epub
2010-00-04
Pages
1973-82
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC2843485
Subset
IM
External Links
PubMed source DOI: 10.2353/ajpath.2010.090486 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2