"Reprogramming the human cancer cell nucleus".
John Frenster 1, , and Jeannette Hovsepian 2
1 Department of Medicine, Stanford University, Stanford,
CA 94027-5446
2 Department of Radiology, Stanford University,
Stanford, CA 94027-5446
The human cancer cell nucleus contains 46 or more chromosomes, each bearing portions of the human genome. During the initiation and progression of the neoplastic state, chromosome portions can be duplicated, deleted, translocated, or inverted, and these lesions often aggravate the rate of progression and metastasis of the cells. During gene transcription, two or more chromosomes may form gene clusters at specific gene sites, and such clusters regulate the rate of gene transcription and replication. Gene clusters are often sensitive to the immediate effects of ligand microRNAs (miRNAs) and other transcribed ultra-conserved noncoding RNAs (T-UCRs). Recent studies have reported 481 species of T-UCRs within human neuroblastoma cells, mostly from intragenic exon and/or intron sequences within the Ref-Seq genome, but 37% were found transcribed from noncoding intergenic sites in the neoplastic cell genome [1]. In 237 of the 481 T-UCRs, intra-nuclear functions were completely independent of those within coding and other nuclear RNAs, and were increased in neuroblastomas of an aggressive type. Most of the T-UCRs could be found in linked regions of 4 major gene clusters, associated with the 4 nuclear processes of neoplastic proliferation, apoptosis, differentiation, and patient survival. Similar T-UCR RNA patterns in normal human fibroblast BJ cells were also observed [1]. Earlier observations had demonstrated a specific deficiency of let-7 RNA microRNA species within human lung and breast neoplasms, that was reversed by the addition of let-7 RNA species to the neoplastic cells in culture [2, 3].
Conclusion:
It appears that microRNAs and perhaps T-UCRs may well be able to reverse the neoplastic state within animals with metatstatic neoplasms, and these RNAs can be delivered as liposomal exosomes [4].
References:
1. Mestdagh E, et al, An integrative genomics screen uncovers ncRNA
T-UCR functions in neuroblastoma tumours. Oncogene
2010 29: 3583-3592.
2. Takamizawa J, et al, Reduced Expression of the let-7 MicroRNAs
in Human Lung Cancers in Association with Shortened Postoperative Survival.
Cancer
Res 2004 64: 3753-3756.
3. Kumar MS, et al, Suppression of non-small cell lung tumor development
by the let-7 microRNA family. Proc
Natl Acad Sci USA 2008 105: 3903–3908.
4. Kosaka N, et al, Secretory Mechanisms and Intercellular Transfer
of MicroRNAs in Living Cells.
J. Biol. Chem 2010,
285: 17442-17452.
5. Meisner LF, and Frenster JH,
"In Vivo
Evolution within Radiation-Induced Clones of Human Lymphocytes".
6. Frenster JH, and Hovsepian JA,
"Models of
successive levels of resolution during individual gene transcription".
7. Frenster JH, and Hovsepian JA,
"Micro
RNAs and adult neoplasms of embryonic type".
8. DeCarvalho S,
"Effect of RNA from
Normal Human Marrow on Leukaemic Marrow In-Vivo".
9. A Brief History of Activator RNA:
10. Warren L, Manos PD, Ahfeldt T, Loh Y-H, Li H, Lau F, Ebina W,
Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan
C, Schlaeger TM, and Rossi DJ.
"Highly
Efficient Reprogramming to Pluripotency and Directed Differentiation of
Human Cells with Synthetic Modified mRNA" ,
11. Vogel G,
"New Technique
RiPS Open Stem Cell Field",
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.
http://www.cancerbiophysics.net/
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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For Further Information and Feedback:
Jeannette A. Hovsepian, M.D.
E-mail: frensasc@ix.netcom.com
Phone: +1 650 367 6483