Identification of a Candidate Tumor Suppressor Gene in Human Lung Cancer

Samson T. Jacob, Ph.D.
College of Medicine, Ohio State University
R01ES10874

Background: Tumor suppressor genes are normal genes whose absence or inactivation can lead to cancer. In other words, if a pair of tumor suppressor genes are either lost from a cell or inactivated by mutation or by a process known as methylation, their functional absence can cause cancer. Methylation causes the addition of small chemical units known as methyl groups to a gene. As methyl units accumulate on a gene, the gene become less active and fewer copies of its protein are made. Tumor suppressor genes work by inhibiting the division of cells.

A recent NIEHS-funded study shows that an enzyme that normally alters the activity of other protein molecules in cells may also help prevent cancer. The enzyme is known as PTPRO (protein tyrosine phosphatase receptor-type O). When the gene responsible for producing PTPRO is silenced, as can happen in lung cancer, the amount of the enzyme drops, allowing cells to grow when they shouldn't. PTPRO removes phosphate groups from the amino-acid tyrosine found in specific proteins. Some proteins become activated and some become inactivated when phosphate groups are removed. It is likely that the silencing of PTPRO alters the phosphate levels of some of these proteins and helps initiate processes that lead to cancer.

Advance: In this study, Jacob and his colleagues show that the PTPRO gene is silenced gradually by methylation. In this case, silencing of the PTPRO gene causes a drop in the level of the PTPRO enzyme. That, in turn, affects certain proteins that PTPRO acts on, furthering the cancer process. The PTPRO gene was examined for methylation in 43 primary human lung tumors and their matching normal adjacent tissue. Fifty-one percent of the genes isolated from tumor samples were heavily methylated, while the gene in the adjacent normal tissue was essentially methylation-free. When the researchers modified laboratory-grown human lung-cancer cells to over-produce the PTPRO enzyme, the cells proliferated more slowly and more often died from apoptosis. In addition, when the researchers used a chemical to remove the methylation in a cancer-cell line, it slowed the growth of the cells, again suggesting that the presence of the PTPRO enzyme slowed the cancer process.

Implications: Taken together, the evidence strongly suggests that the PTPRO gene is a tumor suppressor gene. If further research verifies the importance of the PTPRO gene to the cancer process, it may mean that measuring the degree of methylation of this gene in a patient's tumor will tell doctors something about the level of danger posed by that tumor or whether the tumor is responding well to treatment. The researchers are now working to identify the proteins that the PTPRO enzyme interacts with, and they are analyzing samples from a wide range of cancers to learn which ones also show silencing of the PTPRO gene. This appears to be the first report of an enzyme also serving as a tumor suppressor. This discovery may offer a new target for cancer therapy and may lead to new ways to diagnose some cancers and determine a patient's prognosis and response to treatment.

Citation: Motiwala T, Kutay H, Ghoshal K, Bai S, Seimiya H, Tsuruo T, Suster S, Morrison C, Jacob ST. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13844-9. Epub 2004 Sep 08.