Gene thought to promote cancer suppresses it instead

Washington, July 8 : In a surprising study, scientists at UT Southwestern Medical Center have found that a protein previously believed to promote colorectal cancer, TCF7L2, instead suppresses the growth of human cancer cells.

"This finding reshapes a fundamental model of how colorectal cancer arises," said Dr. Lawrence Lum, assistant professor of cell biology at UT Southwestern and senior author of the study, which appears online today and in a future issue of the Proceedings of the National Academy of Sciences.

The researchers set out to identify genes that contributed to a biochemical malfunction that arises from mutations in the TCF7L2 gene, and accounts for about 90 per cent of colorectal cancers.

They used the genetic screening approach RNAi mediated interference for the purpose.

The researchers employed more than 80,000 small snippets of chemically synthesized RNAs (ribonucleic acids) known as "small interfering RNAs (siRNAs)," which are each capable of inactivating a specific gene.

The researchers mixed the siRNAs with specially engineered human cancer cells that glowed when the cancer-causing malfunction was activated.

When an siRNA made a cell glow, the researchers were able to flag the gene as a candidate cancer gene.

During the gene examination process, the researchers unexpectedly found that the TCF7L2 gene suppressed malignant cell growth rather than promote it.

When the researchers inactivated the gene, human colorectal cancer cells grew more rapidly in culture and emitted a stronger glow.

"The function of TCF7L2 in cancer was previously determined from studies in animals but no one has genetically tested its role in human colorectal cancer cells before. Prior to the advent of RNAi technology, this was very difficult to do in human cultured cells," said Dr. Lum, who is a Virginia Murchison Linthicum Scholar in Medical Research.

The researchers say that the next step is to gain a better understanding of all the steps in the biochemical pathway involved in controlling the action of TCF7L2, which may in turn help identify new therapeutic targets for treating colorectal cancer.

Dr. Lum believes that therapeutic strategies derived from such studies may also be useful in treating type II diabetes, for which risk is strongly associated with mutations in TCF7L2.

ANI