WASHINGTON, DC—MicroRNAs (miRNA) are non-coding RNAs that regulate gene expression and have been implicated in increased malignant state or metastatic growth. Just how strong the association is was demonstrated by four miRNA studies highlighted in a news conference here at the American Association for Cancer Research Annual Meeting.
The studies showed that:
* Overexpression was strongly associated with poorer prognosis in patients with colorectal cancer, especially African-Americans.
* miRNA activity appears to facilitate the movement of melanoma cells across the blood-brain barrier.
* MiRNAs can repress specific tumor suppressors increasing tumorigenicity in lung cancer.
* Resistance to trastuzumab is linked to overexpression of miRNA in breast cancer.
“These are very striking examples relating miRNAs to different types of malignant conditions and poor outcomes,” said the moderator of the news conference, Phillip A. Sharp, PhD, Institute Professor of the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology.
Dr. Sharp, a pioneer in miRNA research and winner of the Nobel Prize for Physiology or Medicine in 1993 for his co-discovery of gene splicing, noted that the AACR had chosen these four papers by researchers who are early in their scientific careers.
“It was appropriate that four young, promising scientists were called to discuss their miRNA research because the field of miRNA is also so very new,” he said.
Dr. Sharp called miRNA “really quite stunning as a subject, in the sense that we really did not know miRNAs were present in cells until about 2001.”
Since then, he said, it has been learned that miRNAs control about half of all the genes that are expressed in human cells.
“This fundamental part of a cellular system changes in cancer, and we didn't know that until about eight years ago. It's like knowing you have a car with four wheels and an engine and a steering wheel but not knowing there is a transmission in the middle—it is that fundamental.”
Each human cell has 500 to 1,000 miRNAs, he continued. But miRNAs are only 20 units long, easy to produce in the laboratory and specific in their functions, so they might be modulated and introduced into cells in the future for therapeutic effect.
Possible Prognostic Tool in Colorectal Cancer
In one of the studies, overexpression of miRNA was found to be strongly associated with poorer prognosis in colorectal cancer. Also found was that overexpression of certain miRNAs is associated with shortened survival in African-Americans with colorectal cancer compared with a similar group of non-Hispanic Caucasian patients.
The study, from the University of Alabama at Birmingham Comprehensive Cancer Center, identified increased expression of miRNAs 21, 106a, 181b, and 203 as associated with poor prognosis.
And miRNA-181b and 203 are specifically associated with shortened survival in African-Americans, said Liselle Bovell, a graduate student in the Department of Pathology.
The study included 218 tissue samples tested, from 104 African-American and 114 non-Hispanic Caucasian colorectal cancer patients, and benign epithelial tissue samples from controls.
The findings suggest that patient race and ethnicity should be considered among other factors in the evaluation of clinical utility of miRNAs, she said.
After the news conference, principal investigator Upender Manne, PhD, Associate Professor of Pathology, said that if the findings are validated in larger studies, that it may be possible to add the molecules to the panel of molecules that are distinctly different between African-Americans and Caucasians and that are contributing to clinical outcomes.
Promoting Melanoma Mets in Brain
Another prognostic potential of miRNAs is in identifying patients with early melanoma who have a higher risk of developing brain metastases, according to researchers from New York University.
“Several miRNAs associated with brain metastasis are found differentially expressed in the corresponding primary tumors, and are important mediators of melanoma metastasis,” said Eva M. Hernando, PhD, Assistant Professor of Pathology and Co-director of the MD/PhD Program at NYU School of Medicine and a member of the NYU Cancer Institute.
“Identification of this signature at the time of diagnosis may contribute to select patients at higher risk for intensified surveillance.”
Dr. Hernando said that while some miRNAs increase the metastatic potential of melanoma cells and the cell's ability to adhere to brain endothelial cells, other miRNAs contribute to the ability of melanoma cells to pass through the blood brain barrier.
MiRNA Represses Tumor Suppressors
It is known that miRNAs can block the action of specific tumor suppressors, and such is the case with miRNA-31 in lung cancer, reported Xi Liu, PhD, a postdoctoral fellow now at the National Cancer Institute. His study, conducted while a graduate student in Toxicology and Pharmacology at Dartmouth School of Medicine, showed that miRNA-31 was overexpressed in malignant lung tissues compared with normal lung tissues.
The research also showed that miRNA-31 targets two tumor suppressors, LATS2 and PPP2R2AA. Expression of miRNA-31 was inversely related to LATS2 and PPP2R2A in both mouse and human lung cancers— On the other hand, though, “knock-down of miRNA-31 suppressed lung cancer growth and tumorigenicity,” he said.
Resistance to Trastuzumab Linked to miRNA
In another study highlighted, scientists at the University of Texas M. D. Anderson Cancer Center identified an miRNA that could potentially distinguish between breast cancer patients who will response to trastuzumab and those who will not.
Samaiyah K. Rehman, a graduate student in the laboratory of Dihua Yu, MD, PhD, Professor and Director of the Cancer Biology Program, reported that breast cancer cells with increased miRNA-21 and reduced PTEN expression were significantly more resistant to trastuzumab (Herceptin) than control cells were.
“High levels of miRA-21 were significantly correlated with poor response to Herceptin,” Rehman said.
Summing up at the conclusion of the news conference, Dr. Sharp noted that three of the four studies found overexpression of miRNA correlating with drug resistance, increased metastasis to the brain, and decreased survival—“This offers the possibility that you could potentially interfere with that miRNA by using an anti-miRNA,” he said. “It's very challenging; we can do this in our mouse models, but when we start doing it in people, it's a challenge.”
Outstanding Achievement in Cancer Research Award Winner Joshua Mendell: Cancer Treatment Opportunities in Both Restoration & Inhibition of MiRNAs
The scientist chosen to receive this year's AACR Award for Outstanding Achievement in Cancer Research Award here at this year's AACR Annual Meeting spoke in his accompanying lecture about the possibilities for using microRNAs as a target in anticancer therapies.
Joshua T. Mendell, MD, PhD, Associate Professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute Early Career Scientist, was recognized for his outstanding work in the identification and characterization of miRNA in cancer. The award is given to scientists age 40 or younger.
“We can confidently say that specific changes in miRNA expression or function can directly contribute to cancer formation, much in the same way that classic oncogenes and tumor suppressors are known to contribute,” he said in his talk.
MicroRNAs could be targeted to the typical lesions known to activate oncogenes, such as amplification, or they could be used to inactivate tumor suppressors by deletion or methylation, he explained.
Dr. Mendell is recognized for discovering that high levels of the Myc protein result in activation of a specific group of miRNAs that drive cellular proliferation and prevent apoptosis. He has since found that excessive amounts of Myc also lead to repression of a large set of miRNAs that normally slow tumorigenesis.
If researchers can identify miRNAs that specifically contribute to tumorigenesis, he said, the question then is whether they can be perturbed or have their normal expression rescued as a new strategy for cancer therapy.
“It's very possible that restoration of expression of miRNAs whose expression is reduced in tumors could be an effective treatment,” he said.
Since some miRNAs, such as miRNA-26a, are expressed at high levels in most or all tissues but also can be downgraded in cancer cells, systemic delivery of such miRNAs may specifically affect cancer cell proliferation and survival while sparing normal cells.
Another intriguing possibility is using oligonucleotide therapy to inhibit miRNAs that are amplified in cancer, such as the oncogenic miRNA-17-92 cluster that is directly induced by Myc.
“Our data on therapeutic potential in the mouse are very encouraging and we're hopeful that it can be used in cancer, especially in those cancers where there are few therapeutic options.”
He said his institution is now collaborating with Ohio State to seek funding for a clinical trial of miRNA therapy.