UIC researchers discover gene that causes liver cancer in animals

When the gene, called Foxm1b, was deleted from liver cells in laboratory mice, the animals failed to develop tumors. Even when the researchers attempted to induce the formation of these tumors artificially, using a standard laboratory technique, the mice remained cancer free.

“To my knowledge, this is the first time a gene has been directly linked to the growth of cancer cells in live animals,” said Robert Costa, professor of biochemistry and molecular genetics in the UIC College of Medicine and the lead investigator in the study.

Results of the study are published in today’s issue of Genes and Development, the premier peer-reviewed journal on molecular genetics and biology.

Earlier studies had shown that Foxm1b is crucial for tissues to repair and replenish themselves — a finding that led Costa to dub it the “fountain-of-youth gene.” When it is absent, the genetic instructions inside a cell, called DNA, don’t duplicate and cells have trouble dividing.

Foxm1b, which is stimulated by growth hormone, appears to malfunction in old age and in certain rare diseases that cause premature aging. It is one of a family of genes that controls the entire life cycle of a cell, including its proliferation, maturation and death.

In the current study, scientists in Costa’s lab used genetically altered mice to establish the link between Foxm1b and liver cancer, showing that the gene is essential for the cancerous cells to multiply.

“Foxm1b is expressed in many different kinds of cancer cells, which leads us to believe it plays a key role in promoting the growth of tumors other than liver cancer,” Costa said.

The scientists also created a prototype for a drug that would block Foxm1b activity and starve tumor cells of the protein that Foxm1b manufactures, preventing their multiplication.

The potential drug was a variant of a protein known to suppress tumors, called p19ARF. By attaching a string of arginines, a component of proteins, to a segment of p19ARF that was shown to inhibit Foxm1b, the scientists enabled the tumor suppressor to cross the cell membrane and enter the body of the cancer cells.

“The ’drug’ reduced not only the activity of Fox m1b but also the growth of cancer cell colonies,” Costa said. “We’re extremely excited about this finding because it suggests we might have a therapy for stemming the spread of liver cancer.”

Costa, who has made a career of studying the Fox family of genes, has long puzzled over why Foxm1b is not active in old age. When the gene is out of commission, tissues can’t regenerate, muscles atrophy, and bones thin. For an organism subject to rules of natural selection, the suppression of Fox m1b seemed odd.

With the current findings, however, Costa wonders whether the human body has evolved to curb Foxm1b in old age in an attempt to thwart cancer.

“I know it’s speculative,” Costa said, “but perhaps aging is just an unintended by-product of an adaptive mechanism to stave off cancer and certain death. Perhaps aging is just nature’s way of attacking cancer.”

Other UIC researchers involved in the experiments were Vladimir Kalinichenko, Michael Major, Xinhe Wang, Vladimir Petrovic, Joseph Kuechle, Helena Yoder, Margaret Dennewitz, Brain Shin, Abhishek Datta and Pradip Raychaudhuri.

The study was funded by the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases.