COLLABORATION

Story by Rod Franklin | Photos by Lynn Gorham

Lynne Bemis, PhD, and Dawn Cochrane, PhD,
are two of about a dozen UCCC researchers
working to unlock the mystery of micro-
RNA's role in cancer development and
progression.

Science is at the cusp of a cancer biology revolution. Every day, new papers appear about a new drug target, a new signaling pathway, a new molecule type found within the human genome that could be the next great hope for stopping cancer in its tracks.

University of Colorado Cancer Center scientists are among the growing ranks of genomic researchers working to lay bare the role of microRNA (miRNA), a short, hairpin-shaped molecule that controls gene expression. Studies show miRNA plays a role in cell growth and cell death. It tends to be found at those fragile sites in the human genome where cancers promote amplification or deletion of genetic sequences. And malignant tumors tend to have lower levels of miRNA than normal tissue.

During the past year, several UCCC researchers have made important discoveries about how miRNA impacts melanoma, breast cancer, endometrial cancer and lung cancer. UCCC researchers’ findings offer just a glimpse into how miRNA might be used for diagnosing cancer, determining which therapies will be effective and perhaps treating cancer itself.

A miRNA surge

At last count, nearly a dozen UCCC researchers are investigating the role of miRNA in cancer. Their initial inquiries bring UCCC into the global fraternity of institutions that have devoted increasing attention to miRNA since 2001, when it was first described in a

trio of Science articles. That year, four journal articles discussed miRNA. Publications swelled to 909 last year, and articles specifically dealing with microarray analyses of miRNA— a high-tech way to measure proteins and other molecules inside DNA—increased from 31 in 2004 to 284 in 2007. This wave of fascination owes to the fact that the several hundred miRNA that have been confirmed in humans, plants, mice, fish and flies appear to serve an untold number of roles in how cells work.

When Dawn Cochrane, PhD, came to the University of Colorado Denver from Vancouver two years ago for post-doctoral training in genetics in the cancer research labs of Steve Nordeen, PhD, and Jennifer Richer, PhD, little miRNA research was going on. Now it’s a main focus of her work.

“It’s really only in maybe the last five years that people started to look at (microRNA in) humans,” she said. “If you talk to most miRNA researchers who work with humans, it tends to be they’ve worked on it only for a couple of years.”

Gene on, gene off

Genetic specialists who analyze the white-hat, black-hat roles of cancer-regulating proteins are fascinated by these two RNA types’ ability to interrupt crucial data handoffs.

“There are proteins that are good for cell proliferation and there are proteins that work against cell proliferation,” Cochrane said. “It has to do with the specific proteins you want to target for a given case. You can target proteins that help tumors grow and spread, but there also are proteins that work against those processes.”

In breast cancer, miRNA seems to have a similar duality of purpose. It can impact protein production and suppress tumors in some cases, but quicken tumor growth in others. Cochrane’s study suggested that the presence of miRNA can affect both how cancer progresses and how stubbornly a tumor resists chemotherapy.

She found that endometrial tumors that had low levels of miR-200c also had epithelial cells that didn’t look like normal epithelial cells. This so-called poor differentiation is a hallmark of aggressive tumors. But when she restored miR-200c to higher levels, the cancer cells lost their ability to migrate and invade normal tissue by 89 percent and 81 percent respectively. What’s more, the cells with higher miR-200c expression became more sensitive to chemotherapy agents.  She has reported that miR-200c seems to control the cells’ identity.

“As the cancer progresses, it loses this miRNA, and it starts to look less like an endometrial cell,” she said. “It (cancer) starts to get more aggressive. We found that if we put this miRNA back in, it starts to look more like a normal endometrial cell.”

Bossing the boss

miRNA may fill more of a bit part in melanoma—the deadliest form of skin cancer—which forms in the skin’s pigment-producing melanocyte cells. The MITF gene is the master melanocyte regulator. It controls how the cells develop and is responsible for their long-term survival. If a melanocyte gets damaged, MITF is supposed to help it die. But if MITF expression is low, the damaged melanocytes can become melanoma tumors. How that happens was a mystery until UCCC researchers Lynne Bemis, PhD, and Bill Robinson, MD, solved it.

In a March 2008 Cancer Research article, the  two scientists showed that miRNA-137 regulates how much MITF is expressed in melanocytes. “That doesn’t mean miRNA-137 has a direct impact on the spread of melanoma, but it is surely a signpost that can help us figure out the genetic and chemical pathways of the disease,” said Bemis, associate professor of Medical Oncology at UC Denver.

She said they took a two-pronged approach to find miR-137. “We said, here’s a gene. What’s regulating it? We knew MITF was associated with melanoma. We also knew 1p22 (a spot on MITF) is a region that’s associated with melanoma. We looked at what microRNAs are located there, and sure enough it was miR-137.

“We think that miR-137 is down-regulated as part of the skin’s natural defense mechanism against sun damage. Some people have a mutation that doesn’t allow miR-137 to downregulate correctly. We got lucky because one of our cell lines had that mutation. It really responds differently, and when stimulated with UV, the miR-137 expression goes wild.”

‘Just the beginning’

All these dynamics help justify scientists’ continued exploration of miRNA-based cancer therapies. Diagnostic applications may surface first, given the advantages of miRNA as a biomarker, Bemis said. She points out that each miRNA is “actually a marker for 100 or 200 genes, versus, say, messenger RNA, which is just one marker.”

This spring, Bemis and UC Denver professor of Pathology Wilbur Franklin, MD, received a $120,000 supplement to Franklin’s Early Cancer Detection Network grant to study miRNA’s role in lung cancer. The grant will provide an enormous worldwide resource: a complete survey of miRNA expression in more than 30 lung cancer cell lines. Data from these experiments will be made generally available to whoever wishes to use it for research purposes.

“I think it’s an exciting area of investigation, and it’s especially interesting that we have such a large number of members working on in it,” said Paul A. Bunn., Jr, MD, UCCC director. “If we can identify all of the miRNAs that regulate oncogenes, we can likely get better at selecting patients for targeted agents. We can use this information to develop new therapies. Maybe we can use the information as early disease biomarkers.”

There’s little question that miRNA is multi-talented. It has been shown to play a role in some of the most basic biologic processes, including fat metabolism, diabetes, heart disease, embryonic development, brain development and hormone secretion. Scientists are trying to sort out just when and how this sticky molecule ducks in and out of a cell’s architecture.

And as they work to unravel what sometimes appears to be miRNA’s highly structured sense of whimsy, new methods with a solid grounding in diagnostic and therapeutic genetics may come forward.

“Everyone is convinced that there are so many more molecules like miRNA out there,” Bemis said. “This is just the beginning.”