Like a bounty hunter returning escapees to custody, a cancer-fighting gene converts organ cells that change into highly mobile stem cells back to their original, stationary state, researchers report online at Nature Cell Biology.
This newly discovered activity of the p53 gene offers a potential avenue of attack on breast cancer stem cells thought to play a central role in progression and spread of the disease, according to scientists at The University of Texas MD Anderson Cancer Center.
Long known for monitoring DNA damage and forcing defective cells to kill themselves, p53 also activates bits of RNA that block two proteins, the researchers found. This prevents conversion of epithelial-differentiated cells, which line or cover an organ, into cells that resemble mesenchymal stem cells when stimulated by the TGF-??growth factor.
Mesenchymal cells are mobile adult stem cells that can reproduce themselves and differentiate into a variety of cell types
"Blocking this conversion from epithelial cell to a mesenchymal cell type is important because that change plays an essential role in cancer metastasis," said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology.
Cancer treatment potential
"We found that p53 activates the micro RNA miR-200c, which forces cells that have taken on stem cell traits to revert to epithelial form," Hung said. "Activating this pathway has therapeutic potential to target tumor-initiating cells that have stem cell characteristics."
Research has shown that about 80 percent of all solid tumors begin in the epithelial cells. However, 90 percent of cancer deaths are caused by metastasis, the progression and spread of the disease to other organs.
The epithelial-to-mesenchymal transition (EMT) and its opposite process play important roles in embryonic development. Research has connected EMT activation to cancer progression and metastasis. Recent studies tie EMT to gain of stem cell traits in normal and transformed cells.
Cell status depends on p53, miR-200c levels
A series of experiments established that the p53 protein activates the miR-200c gene to produce the microRNA and that expression of the protein and miR-200c moved up and down together.
Knockout experiments in normal breast epithelial cells consistently showed that p53 expression stifled the EMT transition.
Cells with reduced p53 changed into mesenchymal-like cells.
When miR-200c was overexpressed in cells with low levels of p53, the cells took on epithelial characteristics, indicating that p53 uses the microRNA to block or reverse the transition to mesenchymal-type cells.
Mutated p53 failed to produce miR-200c, increasing stem cells in the cell culture.
Tissue array analysis of gene expression in 106 human breast tumor samples showed that low p53 expression correlated with higher expression of two genes associated with EMT. Increased p53 raised levels of miR-200c and the expression of a gene associated with epithelial status.
Mutations of p53 occur in more than half of cancers and loss of p53 activity correlates with poor prognosis in several cancer types. Restoring functions lost by p53 mutation by re-expressing miR-200c might be a good therapeutic strategy for treatment of p53-deficient tumors, Hung said.
Research was funded by grants from the National Cancer Institute, including those for MD Anderson's Specialized Program in Research Excellence (SPORE) for breast cancer and MD Anderson's cancer center support grant; the National Breast Cancer Foundation, Inc.; the Breast Cancer Research Foundation; the MD Anderson-China Medical University and Hospital Sister Institution Fund; the National Science Council of Taiwan and the Cancer Research Center of Excellence, Taiwan Department of Health.
Co-authors with Hung, who also is MD Anderson vice president of basic research, are co-lead authors Chun-Ju Chang, Ph.D., and Chi-Hong Chao, Ph.D., Weiya Xia, M.D., Jer-Yen Yang, Ph.D., Yan Xiong, M.D., Chia-Wei Li, Ph.D., Wen-Hsuan Yu, Sumaiyah Rehman, Jennifer Hsu, Ph.D.,, Heng-Huan Lee, Mo Liu, Chun-Te Chen and Dihua Yu, M.D., Ph.D.
Yu, Rehman, Lee, Liu and Chen are graduate students in The University of Texas Graduate School of Biomedical Sciences, a joint operation of MD Anderson and The University of Texas Health Science Center at Houston (UTHealth).
Scott Merville | EurekAlert!
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering