"Analysis of Intra-Nuclear Entropy Changes during EMT Activation".
John H. Frenster 1 and Jeannette A, Hovsepian 2
Divisions of 1 Medical Oncology and 2
Diagnostic
Imaging
Stanford University School of Medicine, Stanford, California 94305
USA
Supported in part by a USPHS Research Career Development Award CA-17857 from the National Cancer Institute.
E-mail: frensasc@ix.netcom.com
Phone: 650/367-6483
During EMT initiation within adult neoplastic cells, former embryonic gene networks are re-activated, often without pre-birth embryonic control factors. In these circumstances, the newly-actived embryonic genes tend to compete with each other, while the newly-transformed nuclear context now acts as a selection mechanism for further neoplastic progression.
The cascade kinetics of such network processes can be conveniently analyzed by entropy changes within the nucleus (Cook PR and Marenduzzo D, "Entropic organization of interphase chromosomes", Journal of Cell Biology, Vol. 186, No. 6, 825-834 (2009), as modified by force calculations of euchromatin within the cell nucleus (Hovsepian JA, and Frenster JH, "Euchromatin as an Extensile Force within Mammalian Cell Nuclei", Molec. Biol. Cell, vol. 14, supp. p. 93a (November, 2003).
The conversion of heterochromatin to euchromatin within the tranformed nucleus results in a very large gain in local entropy, essentially rendering the neoplastic progression process inevitable without countervailing forces being applied.
These can be supplied by microRNAs, which have had significant effects in reversing the neoplastic state toward normal activity, as in: Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M, Tuschl T, and Ponzetto C, "The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation", J. Clin. Investigation. vol. 119: no. 8, pp. 2366-2378 (August, 2009), and as reviwed by: Mishra PJ and Merlino G, "MicroRNA reexpression as differentiation therapy in cancer", J. Clin. Investigation, vol. 119: no. 8, pp. 2119-2123, (August, 2009).
The effects of microRNAs against specific oncogenes has been further
illustrated by the negative effects on c-Myc activity by let-7 RNA complexes,
as in; Kim HH, Kuwano Y, Srikantan S, Lee EK, Martindale JL, and Gorospe
M, "HuR recruits let-7/RISC to repress c-Myc expression", Genes
& Development, vol. 23: (15), pp. 1743-1748 (October 22, 2009).
Additional References:
1. Nicodemi M, and Prisco A, (2009).
"Thermodynamic
Pathways to Genome Spatial Organization in the Cell Nucleus".
2. Hovsepian JA, and Frenster JH, (2009).
"Genomic Models
of Functional Embryomas within Adult Neoplastic Cells".
3. Frenster JH, and Hovsepian JA, (2009).
"Functional Embryomas
as a Result of Embryonic Gene Re-expression".
4. Chen TS, Lai RC , Lee MM, Choo ABH, Lee CN, and Lim
SK,
"Mesenchymal stem
cell secretes microparticles enriched in pre-microRNAs".
5. Deng N-J, and Cieplak P,
"Free Energy
Profile of RNA Hairpins: A Molecular Dynamics Simulation Study".
6. Schoenfelder S, Sexton T, Chakalova L, Cope NF, Horton A, Andrews
S, Kurukuti S, Mitchell JA, Umlauf D, Dimitrova DS, Eskiw CH, Luo Y, Wei
C-L, Ruan Y, Bieker JJ, and Fraser P,
"Preferential
associations between co-regulated genes reveal a transcriptional interactome
in erythroid cells".
7. Zhang H, Li Y, and Lai M,
"The
microRNA network and tumor metastasis".
8. Junier I, Martin O, and Képès F, (2010).
"Spatial
and Topological Organization of DNA Chains Induced by Gene Co-localization".
9. Gupta P, Chaffer C, Guo W, Onder T, Scheel C, Lander ES, and Weinberg
RA,
"The epithelial-mesenchymal transition and the stem-cell state",
in:
Special Conference by American Association for Cancer Research
on EMT/MET in Adult Neoplasms.
10. Clarke MF,
"Stem cells and cancer: Two faces of self renewal", in:
Special Conference by American Association for Cancer Research
on EMT/MET in Adult Neoplasms.
11. Katoh M, Shaw C, Xu Q, Van Driessche N ,Morio T , Kuwayama
H, Obara S, Urushihara H, Tanaka Y, and Gad Shaulsky J,
"An orderly retreat: De-differentiation is a regulated process".
Proc. Natl. Acad.
Sci. USA, vol. 101, no. 18, pp. 7005-7010 (May 4, 2004).
12. Frenster JH, and Hovsepian JA, ( 2010 )
"Cellular
Dynamics of Embryomas within Adult Neoplasms".
Conclusions from Embryoma Genomics:
1. Each cell retains all of its embryonic genes for a lifetime.
2. Controls for embryonic genes are often absent in adults.
3. Uncontrolled embryonic genes can replicate wildly.
4. Replicating genes participate in intra-cellular competition.
5. The basis for gene competition is selective transcription.
6. MicroRNAs can reprogram embryomic transcription.
7. Gene reprogramming can produce normal phenotypes.
8. Normal phenotypes can by-pass chromosomal lesions.
9. MicroRNA therapy may need to be permanent.
10. Transplantation of microRNAs could be preferred.
1. Pathways within cell genomes involve a flow of information.
2. Information can flow by direct contact or by third parties.
3. Direct contact within whole genomes is difficult to regulate.
4. DNA-DNA direct contects are influenced by agents.
5. Nuclear agents include hydrophilic ionic and hydrophobic conforming ligands.
6. Third parties within genomes involve RNAs and proteins.
7. RNAs and proteins are easy to regulate or reverse.
8. Information can be shared, lost, or transformed.
9. System information can be hidden during system isolation.
10. Local information can be permanently lost during system entropy.
Links to Current
Research in Euchromatin:
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:
Links to Medical
Systems Biology:
Links to Selective
Gene Transcription:
Links to RNA-Induced
Epigenetics:
Links to RNA-Induced
Embryogenesis:
Links to RNA and
Biological Causality:
Links to Reprogramming
and Neoplasia:
A Brief History of Activator RNA:
"Ultrastructural
Probes of Active DNA Sites, and the RNA Activators of DNA".
(PowerPoint Presentation).
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Network - Euchromatin
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For Further Information and Feedback:
Jeannette A. Hovsepian, M.D.
E-mail: frensasc@ix.netcom.com
Phone: +1 650 367 6483