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!
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research