Unexpected Link Between Cancer and Diabetes Revealed

New study connects the cancer gene Lin28 to glucose metabolism; may shed light on unifying principles in type 2 diabetes

BOSTON, Sept. 29, 2011 /PRNewswire-USNewswire/ -- A pathway activated in cancer plays an unexpected key role in metabolic diseases like type 2 diabetes, according to a study by researchers at Children's Hospital Boston. Evidence that the Lin28/let-7 pathway influences the cellular response to glucose provides a unifying theme to perplexing data that associates human genetic variation with diabetes risk.

The multi-institutional research team led by George Q. Daley, MD, PhD, director of Stem Cell Transplantation and a leader in the Stem Cell Research Program at Children's Hospital Boston – reported their findings in the September 30 issue of the journal Cell.

Let-7 is a microRNA, a small RNA that dampens the expression of a large set of genes related to cell growth and development. Previously, the Daley lab reported that Lin28, an RNA-binding protein found at high levels in the embryo, blocks let-7 production and is aberrantly expressed in about 15% of all cancers.

"The relationship between Lin28 and let-7 is ancient, found in organisms as diverse as worms, mice, and humans," said Daley, a professor of biological chemistry and molecular pharmacology at Harvard Medical School and a Howard Hughes Medical Institute investigator. "This suggested to us that the Lin28/let-7 pathway was profoundly important, but we didn't expect such exciting results."

In the current study, Daley and his team, led by Hao Zhu and Ng Shyh-Chang, set out to study cancer by developing a trio of mouse models with altered expression of Lin28 and let-7. What they discovered, instead, were profound effects on glucose metabolism. When fed a high-fat diet, normal mice develop obesity and diabetes, but mice engineered to express surplus Lin28 remained lean and processed glucose efficiently while mice engineered to express surplus let-7 became diabetic even on a normal diet.

"The results were startling," said Daley. "Previously we had considered these molecules only as regulators of cell growth and cancer. But in these mice we discovered remarkable effects on sugar processing and diabetes."

Molecular studies showed that Lin28 and let-7 exert their influence on glucose control at multiple points along the evolutionarily ancient insulin signaling pathway. Components of this pathway, which manages growth and glucose metabolism at the cellular level, are also tied to the survival of multiple kinds of cancer.

"Cancer cells have a metabolism that is very embryo-like," Daley noted, "so we speculate that tumors take advantage of the Lin28/let-7 pathway to turn back the clock, in metabolic terms. It's a avenue we'll to study further."

To link their findings in mice to human metabolism, the researchers examined data on genetic variation found in patients with type 2 diabetes together with co-author David Altshuler of Harvard Medical School, a world authority on the genetics of diabetes. They found that many diabetes-associated genes were known or predicted let-7 targets.

"It can be difficult to link genetic association data to actual biochemical pathways in the cell," Daley explained. "Let-7 has hundreds, maybe even thousands, of gene targets. The genetic data, coupled to the striking similarities between the way our mice and patients with diabetes handle glucose argues that regulation by Lin28/let-7 is a unifying feature of many genes associated with diabetes."

The study was supported by the Howard Hughes Medical Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Human Genome Research Institute; the National Institute of General Medical Sciences; the Singapore Agency for Science, Technology, and Research; the American Cancer Society; the American Diabetes Association; the Pew Charitable Trusts, and the Burroughs Wellcome Fund.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Children's, visit: http://vectorblog.org .