"Models of  Embryonic RNA Initiating and Reverting Adult Neoplasms".

John H. Frenster ¹, and Jeannette A. Hovsepian ²,

Divisions of  ¹ Medical Oncology, and of  ² Diagnostic Imaging,
Stanford University School of Medicine, Stanford, California 94305, USA
Phone: 650/367-6483, e-mail:  frensterjh@aol.com ,  hovsepianj@aol.com , http://www.euchromatin.net/

2. Methods: The modelling was based upon an intensive review of the international scientific literature of July 2007 through March 2008. Adult neoplasms selected for simulation included acute myelogenous leukemia, non-small cell carcinoma of the lung, adenocarcinoma of the breast, and Hodgkin lymphoma. The molecular features of the involved embryonic genes, RNAs, and target neoplastic genes were used as the hubs of interaction pathways. The phases of neoplastic initiation and reversion were emphasized, and the results of specific RNA pro- and anti-oncogene actions were evaluated.

3. Results: Interacting RNA molecules consisted chiefly of noncoding RNA species of both the sense and anti-sense orientation. Newly-synthesized RNA was of varied length, from 25-450 nucleotides, inside largely hairpin structures of  significant rigidity. Other, more complex double-stranded RNA structures, were not observed, nor were proteins found to be associated with the noncoding RNAs. Embryonic source genes and target neoplastic genes were both found within active euchromatin microfibrils. When reverting RNAs were found to be deficient, the addition of the missing RNA via plasmid resulted in decreases in growth rate and in tumor load within tumor-bearing animals. There appeared to be a paucity of certain embryonic transcription regulators within the adult cells. Several embryonic genes were newly identified as oncogenes or as anti-oncogenes within the adult neoplasms.

4. Conclusions: Most oncogenes are also expressed normally during embryonic life, and many more normal embryonic genes may also possess oncogenic or anti-oncogenic activity. The activity of embryonic genes is transmitted to target genes via noncoding RNA species. These may function as enhancers to downstream target promoters within adult cells.

Supported in part by a USPHS Research Career Development Award (CA-17857) from the National Cancer Institute. http://www.euchromatin.net/

Table 1: Interactions of sense and antisense RNAs within active euchromatin.
(Frenster JH, "Oncogenes as Molecular Targets within Active Chromatin",
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2. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, and Chang HY,
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3. Shell S, Park S-M, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E, and Peter ME,
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5. Calin GA, Liu C-G, Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE, Shimizu M, Tili E, Rossi S, Taccioli C, Pichiorri F, Liu X, Zupo S, Herlea V, Gramantieri L, Lanza G, Alder H, Rassenti L, Volinia S, Schmittgen TD, Kipps TJ, Negrini M, and Croce CM,
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10. Wang J, Day R, Dong Y, Weintraub SJ, and Michel L,
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11. Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, and Palacios J,
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12. Li J,  and Wang C-Y,
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14. Rinn JL, Wang JK, Allen N, Brugmann SA, Mikels AJ, Liu H, Ridky TW, Stadler HS, Nusse R, Helms JA, and Chang HY,
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15. Fabbri M, Garzon R, Andreeff M, Kantarjian HM, Garcia-Manero G, and Calin GA,
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16. Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, and Jacks T,
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17. Podsypanina K, Politi K, Beverly LJ, and Varmus HE,
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18. Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M,  Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, Settleman J, Giovannini M,  and  Jacks T.
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1. Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, and Chang HY,
"Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells",
Cell Stem Cell, Vol 2, 333-344, 10 April 2008.

2. Boyerinas B, Park S-M, Shomron N, Hedegaard MM, Vinther J, Andersen JS, Feig C, Xu J,  Burge CB, and Peter ME,
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3. Morin RD, O’Connor MD, Griffith M, Kuchenbauer F, Delaney A, Prabhu A-L, Zhao Y, McDonald H, Zeng T, Hirst M, Eaves CJ, and Marra MA,
"Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells",
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4. Ye F, Zhou C, Cheng Q, Shen J,  and Chen H,
"Stem cell abundant protein Nanog, Nucleostemin and Musashi1 highly expressed in malignant cervical epithelial cells",
BMC Cancer April 18, 2008, 8:108, doi:10.1186/1471-2407-8-108.

5. FowlkesCC, Luengo Hendriks CL, Keränen SVE, Weber GH, Rübel O, Huang M-Y, Chatoor S, DePace AH, Simirenko L, Henriquez C, Beaton A, Weiszmann R, Celniker S, Hamann B, Knowles DW, Biggin MD, Eisen MB,, and Malik J,
"A Quantitative Spatiotemporal Atlas of Gene Expression in the Drosophila Blastoderm",
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6. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A,  and Weinberg RA,
"An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors".
Nature Genetics 40, 499 - 507 (2008). Published online: 28 April 2008 | doi:10.1038/ng.127

7. Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P, Vukosavljevic T, Whitman SP, Baldus CD, Langer C, Liu C-G, Carroll AJ, Powell BL, Garzon R, Croce CM, Kolitz JE, Caligiuri MA, Larson RA, and Bloomfield CD,
"MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia",
New England Journal of Medicine vol. 358: no. 18, pp. 1919-1928 May 1, 2008.

8. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, and Goodall GJ,
"The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1",
Nature Cell Biology vol. 10, no. 5, pp. 593 - 601 (May, 2008).

9. Li S-D, Chono S, and Huang L,
"Efficient Oncogene Silencing and Metastasis Inhibition via Systemic Delivery of siRNA",
Molecular Therapy vol. 16, no.  5, pp. 942–946 (May, 2008).

10. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, and Rak J,
"Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells",
Nature Cell Biology vol. 10, no. 5, pp. 619 - 624 (May, 2008).

11. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F,  Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, and Weinberg RA,
"The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells".
Cell, vol: 133, pp. 704-715 (May 16,  2008).

12. He C, Hu H, Braren R, Fong S-Y, Trumpp A, Carlson TR, and Wang RA,
"c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo",
Development vol. 135, no. 14, pp. 2467-2477 (June, 2008).

13. Breau MA, Pietri T, Stemmler MP, Thiery JP, and Weston JA,
"A nonneural epithelial domain of embryonic cranial neural folds gives rise to ectomesenchyme",
Published online on May 30, 2008, Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0711344105
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14. Grasser F, Neusser M, Fiegler H, Thormeyer T, Cremer M, Carter NP, Cremer T, and Müller S,
"Replication-timing-correlated spatial chromatin arrangements in cancer and in primate interphase nuclei".
J Cell Sci. 2008 Jun 1;121(Pt 11):1876-86. Epub 2008 May 13.
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15. Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R,  Lander ES,  and  Meissner A,
"Dissecting direct reprogramming through integrative genomic analysis",
Nature vol. 454, no. 7200, pp. 49-55 (July 3. 2008) | doi:10.1038/nature07056;
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16a. Bueno MJ, de Castro IP, de Cedrón MG, Santos J, Calin GA, Cigudosa JC, Croce CM, Fernández-Piqueras J and Malumbres M,
"Genetic and Epigenetic Silencing of MicroRNA-203 Enhances ABL1 and BCR-ABL1 Oncogene Expression",
Cancer Cell, vol. 13, no. 6, pp. 496-506 (June 10, 2008).

16b. RNA therapy may reverse the oncogenicity of fused proteins.
Faber J, Gregory RI, and Armstrong SA,
"Linking miRNA Regulation to BCR-ABL Expression: The Next Dimension ",
Cancer Cell, vol. 13, no. 6, pp. 467-469 (June 10,  2008).

17. Shaffer AL, Tolga Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H,  Zeng Y, Chen B, Epstein J, and Staudt LM,
"IRF4 addiction in multiple myeloma".
Nature vol. 454, no. 7201, pp. 226-231 (July 10, 2008)
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18. Shaughnessy JD,
"Cancer: An unexpected addiction".
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19.  Chen Y-C, Hsu H-S, Chen Y-W, Tsai T-H, How C-K, Wang C-Y, Hung S-C, Chang Y-L, Tsai M-L, Lee Y-Y, Ku H-H, and Chiou S-H,
"Oct-4 Expression Maintained Cancer Stem-Like Properties in Lung Cancer-Derived CD133-Positive Cells".
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20. Efroni S, Duttagupta R, Cheng J, Dehghani JH, Daniel J. Hoeppner DJ, Chandravanu Dash C,  Bazett-Jones DP, Le Grice S, McKay RDG, Buetow KH, Gingeras TR, Misteli T, and Meshorer E,
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21. Schultz J, Lorenz P, Gross G, Ibrahim S, and Kunz M,
"MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth",
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1. Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H, and Takahashi T,
"Identification of Hypoxia-Inducible Factor-1a as a Novel Target for miR-17-92 MicroRNA Cluster",
Cancer Research vol. 68, pp. 5540-5545, (July 15, 2008).
http://cancerres.aacrjournals.org/cgi/content/abstract/68/14/5540

2. Macias-Perez I, Borza C, Chen X, Yan X, Ibanez R, Mernaugh G, Matrisian LM, Zent R, and Pozzi A,
"Loss of Integrin a1b1 Ameliorates Kras-Induced Lung Cancer",
Cancer Research vol. 68, pp. 6127-6135, (August 1, 2008).
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3. Luoa A, Wanga W, Simaa N, Lua Y, Zhoua J, Xua G, Yub H, Wanga S, and Ma D,
"Short hairpin RNA targeting c-FLIP sensitizes human cervical adenocarcinoma Hela cells to chemotherapy and radiotherapy",
Cancer Letters: doi:10.1016/j.canlet.2008.06.026.

4. High-resolution cell lineage and gene  expression traced through embryogenesis.

Murray JI, Bao Z, Boyle TJ, Boeck ME, Mericle BL, Nicholas TJ, Zhao Z, Sandel MJ, and Waterston RH,
"Automated analysis of embryonic gene expression with cellular resolution in C. elegans",
Nature Methods - vol. 5; no. 8, pp. 703 - 709 (August, 2008)
Published online: 29 June 2008; | doi:10.1038/nmeth.1228
http://www.nature.com/nmeth/journal/v5/n8/abs/nmeth.1228.html.

5. Key embryonic stem cell transcription factors promote the ES cell miRNA expression program.

Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, and Young RA,
"Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells",
Cell, vol. 134, no. 3, pp. 521-533 (August 3, 2008). doi:10.1016/j.cell.2008.07.020

6. Mouse ES cell extracts rapidly induce pluripotency genes of human somatic cells.

(Bru T, Clarke C, McGrew MJ, Sang HM, Wilmut I, and Blow JJ,
"Rapid induction of pluripotency genes after exposure of human somatic cells to mouse ES cell extracts ",
Experimental Cell Research, vol. 314, no. 14, pp. 2634-2642 (August 15, 2008).)   doi:10.1016/j.yexcr.2008.05.009

7. Basic Science at the XX International Congress of Genetics, July 12-17, 2008, Berlin, Germany.

Editorial:
"Back to basics in Berlin".
Nature Genetics 40, 1031 (2008)  doi:10.1038/ng0908-1031
http://www.nature.com/ng/journal/v40/n9/full/ng0908-1031.html

At this year's quinquennial International Congress of Genetics, human genetics provided only a fascinating minority of the content of this conference dedicated to illuminating fundamental biological systems and their evolution.

Introduction

In his keynote lecture, Oliver Smithies revisited the lab notebooks that led to his prizewinning work on homologous gene replacement (http://nobelprize.org/nobel_prizes/medicine/laureates/2007/smithies-lecture.html). Soon after he had made the gel system to visualize protein polymorphisms, he came upon the processes of nonhomologous and homologous recombination that generate copy number variation in the human haptoglobin genes, early (1955–1962) instances of phenomena that are only now being investigated on a genome-wide scale.

Evan Eichler presented evidence from comparative genomics of the great apes of the ancestral configuration and surprising evolutionary history of the 17q21.31 inversion (p 1076). The structure and configuration of segmental duplications promotes recurrent inversion of a chromosomal segment that can both re-create the structural polymorphism in a population and sponsor recurrent deletions with associated genomic disorders.

The five-year spacing of the conference is well suited to looking back over whole areas of basic biology the operation of which we once never even suspected. Elizabeth Blackburn originally posed a question about the replication problems presented by the ends of linear chromosomes and picked a model organism that had more chromosome ends than most. She has now followed this line of enquiry right through many experimental systems to assays that measure ways in which environmental stress takes a quantitative toll on human health. The remedy may even be close at hand, as telomerase remains present in a surprising range of adult tissues. Equally broad in its impact on biology is one of the major degradative modes utilized by all eukaryotic cells. Yoshinori Ohsumi presented a comprehensive tour of the enzymology, protein networks and ubiquitin-like tags involved in autophagy in yeast and serum-starved mammalian cells. This process has also been demonstrated to underpin quality control of protein folding, important for neurological function in mammals. But genetic analysis can cut deeply as well as broadly: Richard Axel and colleagues have now identified four levels of neuronal connections from antenna to muscle in the sexually dimorphic cis-vaccenyl acetate pheromone response in Drosophila courtship behavior.

The way in which our understanding of epigenetics and stem cell biology has developed from phenomenology, via genetic screens, to universal mechanisms was exemplified by a talk from Gunter Reuter. In his lab, the classical phenomenon of position-effect variegation was unraveled by screening for modifier mutants, loci which now identify heterochromatin proteins, histone methylases and other 'epigenetic' regulators of gene expression and transposable element silencing. Also at this meeting, Azim Surani reexamined the determination and identity of primordial mammalian germ cells in the era of somatic nuclear reprogramming and the generation of induced pluripotent cells. Allan Spradling explained, using the well-characterized Drosophila ovary with clonal marking of cell lineage, how many of our preconceived ideas about stem cell biology are wrong. Stem cells are not necessarily long-lived, rarely dividing cells with stable identity. Rather, cells de-differentiate under the right dynamic confluence of signals (the stem cell 'niche'), cells can compete for the role of stem cell, and stem cell populations in adjacent developmental compartments are able to coordinate their proliferation and differentiation. Spradling's work raises the questions of how many more proteins of the cell surface and cell-cell interaction (for example beta-catenin and Notch) also have a signaling role in the nucleus, and how many more of these 'structural signallers' remain to be found in key stem cell roles.

Whereas genetics once grew out of agriculture, here, with a preponderance of molecular cell biologists of model organisms in attendance, it is just possible that the possibilities of genomic agricultural genetics might have gone underappreciated. The potential is enormous, as Edward Buckler emphasized when he presented the results and ambitions of the maize diversity project. Quantitative traits such as yield and flowering time are being mapped in millions of plants from among thousands of inbred lines of the world's largest and most diverse crop.

With all the meeting's emphasis on lifetime achievement and the mature analysis of fundamental biological processes, there was still plenty that was breaking new ground. Yijun Ruan laid out some of the new applications of high-throughput paired-end tag sequencing, particularly as it can be applied to copy number variation and epigenetic mapping of transcriptional regulatory regions that form looped and clustered regions of the genome. Michael Axtell made the point that we are no longer limited by DNA sequencing, and is using deep resequencing to mine the cell's pool of degraded mRNA for the targets of evolutionarily conserved microRNAs that directed their degradation. Augustine Kong presented a long-range haplotyping method that promises to be useful in pinpointing the origin of (deleterious and therefore short-lived) founder effect mutations and copy number variations by genotyping only a proportion of the population
(p 1068).

It is of course impossible in a meeting report to cover more than a few of the highlights of an event of this kind, and it will be most exciting to know what the next five years will bring.

8. Canonical  embryonic oncogenic development of Basal Cell Carcinomas.

Yang SH, Andl T, Grachtchouk V, Wang A, Liu J, Syu L-J, Ferris J, Wang TS, Glick AB, Millar SE,  and Dlugosz AA,
"Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/bold beta-catenin signaling",
Nature Genetics vol. 40, no. 9, pp. 1130 - 1135 (September, 2008) ;
Published online: 1 August 2008 | doi:10.1038/ng.192
http://www.nature.com/ng/journal/v40/n9/abs/ng.192.html.

9. Multi-lineage differentiation and replication from colon cancer stem cells.

Vermeulen L, Todaro M, de Sousa Mello, Sprick FMR, Kemper K, Perez Alea M, Richel DJ, Stassi G, and Medema JP.
"Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity".
PNAS September 9, 2008 vol. 105 no. 36 13427-13432
http://www.pnas.org/content/105/36/13427.abstract?etoc.

10. Untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation.

Podsypanina K, Du Y-CN, Jechlinger M, Beverly LJ, Hambardzumyan D, and Varmus H,
"Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung",
Science 26 September 2008: Vol. 321. no. 5897, pp. 1841 - 1844 DOI: 10.1126/science.1161621
http://www.sciencemag.org/cgi/content/short/321/5897/1841.

11. Inflammation-like state accelerates the migration of primary tumour cells to lung tissues.

Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H,  and  Maru Y,
"The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase",
Nature Cell Biology, Published online: 28 September 2008 | doi:10.1038/ncb1794
http://www.nature.com/ncb/journal/vaop/ncurrent/abs/ncb1794.html.

12. Murine leukemia progression and expression of multiple miRNAs.

Kuchenbauer F, Morin RD, Argiropoulos B, Petriv OI, Griffith M, Heuser M, Yung E, Piper J, Delaney A, Prabhu A-L, Zhao Y, McDonald H, Zeng T, Hirst M, Hansen CL, Marra MA, and  Humphries RK,
"In-depth characterization of the microRNA transcriptome in a leukemia progression model".,
Published online before print October 10, 2008, Genome Research, DOI: 10.1101/gr.077578.108

13. Reprogramming of human cancer cells by microRNA.

 (Lin S-L, Chang DC, Chang-Lin S, Lin C-H, Wu DTS, Chen DT, and Ying S-Y,
"Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state".
RNA vol. 14: no. 10, pp. 2115-2124 (October, 2008).

14. Embryonic let-7 microRNA complementary site SNP in KRAS 3' UTR increases Non-Small Cell Lung Cancer risk".

Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller R-U, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, and Weidhaas JB,
"A SNP in a let-7 microRNA complementary site in the KRAS 3' Untranslated Region increases Non–Small Cell Lung Cancer Risk",
Cancer Research 68, 8535-8540, October 15, 2008. doi: 10.1158/0008-5472.CAN-08-2129.

15. xx. Multiple non-uniform asynchronous chromosomal changes during neoplastic progression.

Li X, Galipeau PC, Sanchez CA, Blount PL, Maley CC,  Arnaudo J, PeifferDA, Pokholok D, Gunderson KL, and Reid BJ,
"Single Nucleotide Polymorphism–Based Genome-Wide Chromosome Copy Change, Loss of Heterozygosity, and Aneuploidy in Barrett's Esophagus Neoplastic Progression",
Cancer Prevention Research 1, 413-423, November 1, 2008. doi: 10.1158/1940-6207.CAPR-08-0121)
http://cancerpreventionresearch.aacrjournals.org/cgi/content/abstract/1/6/413?.

16. Short RNA GAS1 suppresses metastases within human melanoma cell lines.

(Gobeil S, Zhu X, Doillon CJ, and Green MR,
"A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene",
Genes & Development. vol.22: no. 21, pp. 2932-2940, (November 1, 2008).
http://genesdev.cshlp.org/content/22/21/2932.abstract ).
 
 

Links to Reprogramming and Neoplasia:

Links to RNA and Biological Causality:

Links to RNA as a Therapeutic Agent:

Links to Euchromatin Activator RNA Reviews:
Links to Euchromatin Activator RNA Research:
Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
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Links to RNA-Induced Epigenetics:
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Links to RNA and Biological Causality:
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A Brief History of Activator RNA:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA". (PowerPoint Presentation).