The discovery, reported online February 21 in ScienceExpress, "provides a key insight into two fundamental processes in biology--stem cell generation and carcinogenesis," says Richard Gregory, PhD, the study's senior author.

Lin-28 regulates the let-7 family of microRNAs, known to be key players in cancers of the lung and breast, and was also recently shown to help reprogram skin cells to pluripotent stem cells resembling embryonic stem cells. Because both cellular reprogramming and carcinogenesis entail cellular de-differentiation (reversion of a mature cell to a less mature state), Lin-28 provides a missing link between stem cell generation and cancer.

Richard Gregory, PhD

In 2006, Scott Hammond's group at University of North Carolina, Chapel Hill, discovered that microRNAs were made as immature forms in embryonic cells and cancer cells, but the mechanism for the blocking of their maturation remained elusive. Srini Viswanathan, a graduate student in the laboratory of George Daley, MD, PhD, at Children's Hospital Boston, was interested in how microRNAs might dictate tissue formation from embryonic stem cells, which show a block in processing of a specific family of microRNAs called let-7.

Viswanathan and Gregory hypothesized that some protein must bind to the immature form of let-7 microRNAs to block their processing, and set out to purify the protein. They identified a number of proteins associated with microRNAs, but only Lin-28 was uniquely expressed in embryonic tissues. They then demonstrated that Lin-28 was directly responsible for the blockade of let-7 microRNA in embryonic cells: expressing Lin-28 in non-embryonic cells reproduced the block in let-7 processing, and inhibiting Lin-28 expression in embryonic tissues caused upregulation of let-7.

The study also provides a key insight into cancer. A characteristic of cancer is low expression of microRNAs. In their paper, Viswanathan, Daley and Gregory show that a close relative of Lin-28, Lin-28b, which has been linked to hepatocellular carcinoma, likewise blocks processing of let-7 microRNAs. Loss of the let-7 microRNA is critical for breast and lung cancer. Therefore, the study suggests that activating Lin-28 may promote cancer formation, whereas blocking it may be protective, the researchers say.

"The discovery of how Lin-28 works was an unexpected 'Eureka' moment," says Viswanathan. "We are looking forward to finding drugs that antagonize Lin-28, as these might be an important weapon against cancer."

The research was funded by Children's Hospital Boston, The Harvard Stem Cell Institute, y the NIH Director's Pioneer Award of the NIH Director's Roadmap for Medical Research.

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 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 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 397-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 the hospital and its research visit: www.childrenshospital.org/newsroom.