Research in the laboratory of Yale scientist Frank J. Slack has identified a new way that a familiar gene is regulated in lung cancer, presenting new possibilities for diagnosis and treatment.

The work is reported in March issues of the journals Cell and Developmental Cell.

The oncogene Ras is out of control in about 20% of cancers where it is over-expressed or activated by mutation. According to Slack, assistant professor of molecular, cellular and developmental biology and a member of the Yale Cancer Center, it is one of the most identifiable causes in some forms of lung cancer. His team has identified let-7, a natural and separately transcribed RNA that maps to a chromosomal region associated with lung cancer as a regulator of Ras expression.

DNA of plants and animals contains sequences encoding microRNAs, important regulators of development, that control processes determining cell type and cell death.

"The let-7 microRNA regulates Ras by binding to the message for Ras and likely inhibits translation of the Ras protein," says Slack. "The microRNA does not revert a mutated Ras to normal; instead it acts like a brake on an accelerated Ras."

Lung cancer currently has a poor prognosis with less than 15% of patients surviving five years. The lungs, however, are relatively accessible for inhalation of potential gene therapy agents. "While this is not likely to cure the cancer," says Slack, "after diagnosis, gene therapy with let-7 may be a way to alleviate or slow it down."

This work arose from Slack's basic research in the Department of Molecular, Cellular and Developmental Biology on the nematode round worms, C. elegans. He found that these worms require let-7 RNA for normal development to occur. Without it, cells do not stop dividing and fail to differentiate into the normal structures of the worm -- instead they make an excess of their cells.

After identifying let-7 as a cell division regulator, Slack's team used bioinformatics and found the relationship to Ras. Let-7 in humans is identical to the sequence in the worm, and both binding site and pathway for Ras are highly conserved.

Tissue from lung cancer tumors, compared with their normal adjacent tissue, had reduced let-7 and increased Ras -- showing the brakes on Ras were removed in lung tumors.

"The discovery of a new aspect of the regulation and targeting of a well-known gene involved with cancer progression will have profound implications as we continue to focus on the causes of tumor development," says Dr. Richard L. Edelson, director of the Yale Cancer Center.

Other Yale researchers were Steven M. Johnson, Helge Grosshans and Kristy L. Reinert; collaborators at Ambion Inc. included Jaclyn Shingara, Mike Byrom, Rich Jarvis, Angie Cheng, Emmanuel Labourier and David Brown. Support for the research came from the Human Frontiers Science Program, the National Institutes of Health and the National Science Foundation.

-- By Janet Rettig Emanuel

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