Ectopic Expression of Oct-4 Blocks Progenitor-Cell Differentiation and Causes Dysplasia in Epithelial Tissues

The POU-domain transcription factor Oct-4 is normally expressed in pluripotent cells of the mammalian embryo. In addition, germ-cell tumors and a few somatic tumors show detectable expression of Oct-4. While Oct-4's role during preimplantation development is to maintain embryonic cells in a pluripotent state, little is known about its potential oncogenic properties. Here we investigate the effect of ectopic Oct-4 expression on somatic tissues of adult mice using a doxycycline-dependent expression system. Activation of Oct-4 results in dysplastic growths in epithelial tissues that are dependent on continuous Oct-4 expression. Dysplastic lesions show an expansion of progenitor cells and increased beta-catenin transcriptional activity. In the intestine, Oct-4 expression causes dysplasia by inhibiting cellular differentiation in a manner similar to that in embryonic cells. These data show that certain adult progenitors remain competent to interpret key embryonic signals and support the notion that progenitor cells are a driving force in tumorigenesis.

[1]  Gerlinde Reim,et al.  Spiel-ohne-grenzen/pou2 mediates regional competence to respond to Fgf8 during zebrafish early neural development. , 2002, Development.

[2]  Randall T Moon,et al.  WNT and beta-catenin signalling: diseases and therapies. , 2004, Nature reviews. Genetics.

[3]  F. Watt,et al.  Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours , 2004, Development.

[4]  Liang Cheng.  Establishing a germ cell origin for metastatic tumors using OCT4 immunohistochemistry , 2004, Cancer.

[5]  Liang Cheng,et al.  OCT4: A Novel Biomarker for Dysgerminoma of the Ovary , 2004, The American journal of surgical pathology.

[6]  M. Grachtchouk,et al.  Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. , 2005, Genes & development.

[7]  I. Weissman,et al.  JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells , 2004, Cell.

[8]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[9]  W. Driever,et al.  spiel ohne grenzen/pou2 is required during establishment of the zebrafish midbrain-hindbrain boundary organizer. , 2001, Development.

[10]  G. Chirn,et al.  Multiple Retropseudogenes from Pluripotent Cell-specific Gene Expression Indicates a Potential Signature for Novel Gene Identification* , 2005, Journal of Biological Chemistry.

[11]  P. Brown,et al.  Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Y. Bergman,et al.  A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells , 1995, Molecular and cellular biology.

[13]  J. Richie.  Establishing a germ cell origin for metastatic tumors using OCT4 immunohistochemistry. , 2005, The Journal of urology.

[14]  Hans Clevers,et al.  Caught up in a Wnt storm: Wnt signaling in cancer. , 2003, Biochimica et biophysica acta.

[15]  I. Kanazawa,et al.  Oct-3/4 repression accelerates differentiation of neural progenitor cells in vitro and in vivo. , 2004, Brain research. Molecular brain research.

[16]  Austin G Smith,et al.  Self-renewal of teratocarcinoma and embryonic stem cells , 2004, Oncogene.

[17]  I. Weissman,et al.  Stem Cells Units of Development, Units of Regeneration, and Units in Evolution , 2000, Cell.

[18]  H. Schöler,et al.  Oct4 distribution and level in mouse clones: consequences for pluripotency. , 2002, Genes & development.

[19]  D. Page,et al.  Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei , 2003, Development.

[20]  Michael F. Clarke,et al.  Applying the principles of stem-cell biology to cancer , 2003, Nature Reviews Cancer.

[21]  C. P. Leblond,et al.  Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. , 1974, The American journal of anatomy.

[22]  M. Fuller,et al.  Orientation of Asymmetric Stem Cell Division by the APC Tumor Suppressor and Centrosome , 2003, Science.

[23]  Liang Cheng,et al.  OCT4 Staining in Testicular Tumors: A Sensitive and Specific Marker for Seminoma and Embryonal Carcinoma , 2004, The American journal of surgical pathology.

[24]  Ian P Newton,et al.  Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. , 2004, Genes & development.

[25]  A. Schnieke,et al.  Production of gene-targeted sheep by nuclear transfer from cultured somatic cells , 2000, Nature.

[26]  J. Roder,et al.  Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Wynshaw-Boris,et al.  The canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation. , 2004, Current opinion in genetics & development.

[28]  K. McGowan,et al.  Onset of Keratin 17 Expression Coincides with the Definition of Major Epithelial Lineages during Skin Development , 1998, The Journal of cell biology.

[29]  H. Schöler,et al.  Oct‐4: Gatekeeper in the Beginnings of Mammalian Development , 2001, Stem cells.

[30]  Y. Bergman,et al.  A Unique Developmental Pattern of Oct-3/4DNA Methylation Is Controlled by a cis-demodification Element* , 2002, The Journal of Biological Chemistry.

[31]  M. T. Hasan,et al.  Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  I. Weissman,et al.  A role for Wnt signalling in self-renewal of haematopoietic stem cells , 2003, Nature.

[33]  D. Salomon,et al.  Cripto: A tumor growth factor and more , 2002, Journal of cellular physiology.

[34]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[35]  D. Skalnik,et al.  Histone deacetylase activity is required for embryonic stem cell differentiation , 2004, Genesis.

[36]  Y. Bergman,et al.  Oct-3/4 is a dose-dependent oncogenic fate determinant. , 2003, Cancer cell.

[37]  H. Varmus,et al.  Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Simonsson,et al.  Nuclei of Adult Mammalian Somatic Cells Are Directly Reprogrammed to oct-4 Stem Cell Gene Expression by Amphibian Oocytes , 2003, Current Biology.

[39]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[40]  Y. Ishikawa,et al.  EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12) , 2005, Genes, chromosomes & cancer.

[41]  Christopher H. Contag,et al.  MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer , 2004, Nature.

[42]  P. Goss,et al.  The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells. , 2003, The Biochemical journal.

[43]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Bob Y. Liu,et al.  The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[45]  I. Weissman,et al.  Therapeutic implications of cancer stem cells. , 2004, Current opinion in genetics & development.

[46]  S. Burgess,et al.  The zebrafish spiel-ohne-grenzen (spg) gene encodes the POU domain protein Pou2 related to mammalian Oct4 and is essential for formation of the midbrain and hindbrain, and for pre-gastrula morphogenesis. , 2002, Development.

[47]  Hans Clevers,et al.  Live and let die in the intestinal epithelium. , 2003, Current opinion in cell biology.

[48]  Austin G Smith,et al.  Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation , 2002, Nature Biotechnology.

[49]  H. Lomelí,et al.  Phenotypic analyses of mouse embryos with ubiquitous expression of Oct4: Effects on mid–hindbrain patterning and gene expression , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[50]  R. Jaenisch,et al.  Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[51]  E. Fuchs,et al.  De Novo Hair Follicle Morphogenesis and Hair Tumors in Mice Expressing a Truncated β-Catenin in Skin , 1998, Cell.

[52]  D. Salomon,et al.  Expression of cripto, a novel gene of the epidermal growth factor gene family, leads to in vitro transformation of a normal mouse mammary epithelial cell line. , 1991, Cancer research.

[53]  D. Felsher.  Reversibility of oncogene-induced cancer. , 2004, Current opinion in genetics & development.

[54]  H. Niwa,et al.  Involvement of Oct3/4 in the enhancement of neuronal differentiation of ES cells in neurogenesis-inducing cultures , 2003, Development.

[55]  Satoshi Tanaka,et al.  Epigenetic Control of Mouse Oct-4 Gene Expression in Embryonic Stem Cells and Trophoblast Stem Cells* , 2004, Journal of Biological Chemistry.

[56]  J. Kononen,et al.  POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. , 2003, Cancer research.

[57]  Ajamete Kaykas,et al.  WNT and β-catenin signalling: diseases and therapies , 2004, Nature Reviews Genetics.

[58]  Hans Clevers,et al.  The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. , 2002, Cell.

[59]  S. Yamanaka,et al.  Role of ERas in promoting tumour-like properties in mouse embryonic stem cells , 2003, Nature.

[60]  M. Rudnicki,et al.  Wnt Signaling Induces the Myogenic Specification of Resident CD45+ Adult Stem Cells during Muscle Regeneration , 2003, Cell.

[61]  L. Looijenga,et al.  Role of gain of 12p in germ cell tumour development , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[62]  H. Schöler,et al.  Mouse germline restriction of Oct4 expression by germ cell nuclear factor. , 2001, Developmental cell.

[63]  Tony Pawson,et al.  β-Catenin and TCF Mediate Cell Positioning in the Intestinal Epithelium by Controlling the Expression of EphB/EphrinB , 2002, Cell.

[64]  H. Schöler,et al.  Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. , 1994, Developmental biology.

[65]  P. Greengard,et al.  Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor , 2004, Nature Medicine.

[66]  C. Holding,et al.  Human embryonic genes re-expressed in cancer cells , 2001, Oncogene.

[67]  I. Gozes,et al.  A vasoactive intestinal peptide receptor analog alters the expression of homeobox genes. , 2002, Life sciences.

[68]  R. Fodde,et al.  Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling , 2002, Nature Genetics.

[69]  C. Bokemeyer,et al.  New insights into the pathology and molecular biology of human germ cell tumors , 2004, World Journal of Urology.

[70]  L. Olson,et al.  Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. , 2004, Carcinogenesis.

[71]  Hans Clevers,et al.  The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells , 2002, Cell.

[72]  Laurie E Ailles,et al.  Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. , 2004, The New England journal of medicine.

[73]  J. Brickman,et al.  Pluripotency and tumorigenicity , 2002, Nature Genetics.

[74]  T. Sun,et al.  Interaction of trichohyalin with intermediate filaments: three immunologically defined stages of trichohyalin maturation. , 1992, The Journal of investigative dermatology.

[75]  R. McKay,et al.  Hybrid cell extinction and re‐expression of Oct‐3 function correlates with differentiation potential. , 1993, The EMBO journal.

[76]  M. Bienz.  Faculty Opinions recommendation of Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. , 2002 .

[77]  Elaine Fuchs,et al.  Stem cells of the skin epithelium , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[78]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[79]  M. Rosenfeld,et al.  POU domain family values: flexibility, partnerships, and developmental codes. , 1997, Genes & development.

[80]  P. Goss,et al.  Examination of POU homeobox gene expression in human breast cancer cells , 1999, International journal of cancer.

[81]  Anjen Chenn,et al.  Regulation of Cerebral Cortical Size by Control of Cell Cycle Exit in Neural Precursors , 2002, Science.

[82]  T. Sun,et al.  Acidic and basic hair/nail ("hard") keratins: their colocalization in upper cortical and cuticle cells of the human hair follicle and their relationship to "soft" keratins , 1986, The Journal of cell biology.

[83]  M. Tada,et al.  Histone Code Modifications on Pluripotential Nuclei of Reprogrammed Somatic Cells , 2004, Molecular and Cellular Biology.

[84]  Hans Clevers,et al.  Armadillo Coactivates Transcription Driven by the Product of the Drosophila Segment Polarity Gene dTCF , 1997, Cell.

[85]  H. Schöler,et al.  Oct4 is required for primordial germ cell survival , 2004, EMBO reports.

[86]  A. Clark,et al.  Human STELLAR, NANOG, and GDF3 Genes Are Expressed in Pluripotent Cells and Map to Chromosome 12p13, a Hotspot for Teratocarcinoma , 2004, Stem cells.

[87]  Norio Nakatsuji,et al.  Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells , 2001, Current Biology.