Malfunctioning Tumor Suppressor Genes Spur Growth of Liver Cancer

Cancer researchers have combined genomics, RNA interference, and mosaic mouse models to track down and identify a group of tumor suppressor genes that fails to operate in liver cancer cells.

Investigators at Cold Spring Harbor Laboratory (NY, USA) began by compiling pools of short hairpin RNAs (shRNAs) that specifically blocked the activity of the mouse orthologs of genes recurrently deleted in a series of human liver cancers. Assuming that some of these shRNAs would inhibit tumor-suppressing genes, they tested the ability of the shRNAs to promote tumorigenesis in a mosaic mouse model.

They reported in the November 13, 2008, issue of the journal Cell that they had identified and validated 13 tumor suppressor genes, 12 of which had not been linked to cancer before. One gene, XPO4, encoded a nuclear export protein whose substrate, EIF5A2, was amplified in human tumors, was required for proliferation of XPO4-deficient tumor cells, and promoted liver cancer in mice.

"Apparently, there is a high incidence of cancer genes that are physically next to each other in the genome,” explained senior author Dr. Scott Lowe, professor of cellular and molecular biology at Cold Spring Harbor Laboratory. "It may explain why cancer is so heterogeneous; there are a lot of possible combinations to get there. It is important to understand all the genetic alterations that can give rise to cancer. If we understand cancer, we can treat it better by going after the molecular causes or by categorizing cancers to better predict their behavior.”

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Cold Spring Harbor Laboratory