Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

When oxygen is short, EGFR prevents maturation of cancer-fighting miRNAs

24.05.2013
With tumor suppressors frozen in adolescence, resistant cancer cells cheat death

Even while being dragged to its destruction inside a cell, a cancer-promoting growth factor receptor fires away, sending signals that thwart the development of tumor-suppressing microRNAs (miRNAs) before it's dissolved, researchers reported in an early online publication at Nature.

Under conditions of oxygen starvation often encountered by tumors, the epidermal growth factor receptor (EGFR) gums up the cell's miRNA-processing machinery, an international team led by scientists at The University of Texas MD Anderson Cancer Center discovered.

"So when hypoxia stresses a cell, signaling by EGFR prevents immature miRNAs from growing up to fight cancer," said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology and holder of the Ruth Legett Jones Distinguished Chair.

The group's findings point to a potential new prognostic marker for breast cancer, Hung noted, but also provide the first evidence of a growth factor signaling pathway regulating miRNA maturation.

"Inside of a cell, you have signal induction, in this case through EGFR, and you also have a protein complex that processes precursors into mature miRNA to perform a function. They didn't appear to talk to each other, it's as if one speaks English and the other Chinese," Hung said. "This is the first paper to show how they communicate."

The scientists established the relationship in cell line experiments, confirmed it in a mouse model and human breast cancer samples, then found that it reduced breast cancer patient survival in a review of 125 cases.

A new cancer-promoting role identified for EGFR

EGFR penetrates the cell membrane to receive signals from growth factors outside of the cell. After a growth factor binds to it, EGFR conveys the signal into the cell by attaching phosphate groups to other proteins, often acting as a molecular "on switch."

In many cancers, EGFR is overexpressed or dysfunctional, constantly sending signals to cells to divide. Hung and colleagues found that EGFR also fuels cancer progression by stifling tumor-suppressing miRNAs.

As a tumor grows, large portions of its interior can become starved for oxygen (hypoxia) for lack of adequate blood vessels. This stress suffocates many tumor cells, but the few that endure become highly malignant, resist treatment and are most likely to spread, Hung said.

Anti-angiogenesis drugs designed to kill tumors by blocking their ability to spin webs of supportive blood vessels often succeed at first, Hung said, but then fail against the more malignant cells that survive hypoxia.

When hypoxia hits, EGFR gets active and gets eaten

Low-oxygen conditions cause EGFR overexpression. EGFR also is pulled into the cell interior, captured in cavities called vesicles and eventually fed into lysosomes, a membrane-enclosed organelle loaded with enzymes to dissolve proteins.

It was known that EGFR continues to signal even while caught in the vesicles, which actually prolongs its activation. Hung and colleagues found that EGFR signals to a key protein in miRNA processing called argonaute 2, or AGO2.

AGO2 connects with two other proteins called Dicer and TRBP to form a complex that processes microRNA precursors into mature miRNAs, which regulate gene expression after messenger RNA has been expressed but before it's translated into a protein.

Oncoprotein-regulating miRNAs don't grow up

The scientists found that EGFR attaches phosphate groups to AGO2, which in turn weakens AGO2's ability to connect with Dicer to produce mature microRNAs. EGFR's effect is stronger during oxygen starvation than under normal conditions.

The team identified a number of specific miRNAs affected by EGFR, most of which have been reported to have tumor suppressor characteristics. The miRNAs regulated by phosphorylated AGO2, including miR-31, miR-192 and miR-193a-5p, also shared a long-loop structure in their precursors that miRNAs unaffected by AGO2 phosphorylation lack.

Hypoxic environments around tumors promote metastasis by helping cells evade programmed cell death. Hung and colleagues showed that EGFR-mediated AGO2 phosphorylation blocks cell death and enhances invasiveness under hypoxia.

Experiments in a mouse model of breast cancer confirmed that expression of EGFR and the presence of phosphorylated AGO2 increase during tumor progression under oxygen-starved conditions.

EGFR-AGO2 connection found in human breast tumors; reduces survival

The hypoxia-EGFR-AGO2 connection was strong in tumor samples from 128 breast cancer patients, but it was low or absent in normal breast tissue. In 125 breast cancer cases analyzed by the team, half of 62 patients with high levels of phosphorylated AGO2 survived to 48 months and beyond. Median survival had not been reached for the 63 patients in the low-level group, but 78 percent had survived to 48 months.

"One can imagine other receptors for platelet-derived growth factor and insulin-like growth factor also regulating miRNAs, perhaps by regulating Dicer or TBRP," Hung said. "This is a turning-point paper; it will induce lots of new questions for scientists to pursue."

Co-authors with Hung are lead author Jia Shen, Weiya Xia, M.D., Yekaterina Khotskaya, Ph.D., Longfei Huo, Ph.D., Seung-Oe Lim, Ph.D., Yi Du, Ph.D., Yan Wang, Ph.D., Jennifer Hsu, Ph.D., and Yung Carmen Lam, Ph.D., all of MD Anderson's Department of Molecular and Cellular Oncology; Wei-Chao Chang, Ph.D., of China Medical University, Taichung, Taiwan, and Chung-Hsuan Chen, Ph.D., of Genomics Research Center of Academica Sinica, Taipei; Yun Wu, M.D., Ph.D., of MD Anderson's Department of Pathology; Brian James, Ph.D., Xiuping Liu, M.D., and Chang-Gong Liu, Ph.D., of MD Anderson's Department of Experimental Therapeutics; and Kotaro Nakanishi, Ph.D., and Dinshaw Patel, Ph.D., of Memorial Sloan-Kettering Cancer Center.

Shen is a graduate student at The University of Texas Graduate School of Biomedical Sciences at Houston, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.

This research was funded by grants from the U.S. National Institutes of Health (CA109311 and CA099031), MD Anderson's Cancer Center Support Grant from the National Cancer Institute (CA16672), the U.S. National Breast Cancer Foundation, MD Anderson's Center for Biological Pathways, Susan G. Komen for the Cure, the Sister Institution Fund of China Medical University and Hospital and MD Anderson, the Taiwan Cancer Research Center of Excellence, a Private University grant from Taiwan and the Taiwan Program for Stem Cell and Regenerative Medicine Frontier Research.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Life Sciences:

nachricht Copper hydroxide nanoparticles provide protection against toxic oxygen radicals in cigarette smoke
29.05.2017 | Johannes Gutenberg-Universität Mainz

nachricht Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Strathclyde-led research develops world's highest gain high-power laser amplifier

The world's highest gain high power laser amplifier - by many orders of magnitude - has been developed in research led at the University of Strathclyde.

The researchers demonstrated the feasibility of using plasma to amplify short laser pulses of picojoule-level energy up to 100 millijoules, which is a 'gain'...

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

Camera on NASA's Lunar Orbiter survived 2014 meteoroid hit

29.05.2017 | Physics and Astronomy

Strathclyde-led research develops world's highest gain high-power laser amplifier

29.05.2017 | Physics and Astronomy

A 3-D look at the 2015 El Niño

29.05.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>