Miguel Villalona, MD
A newly identified protein that can flag an important tumor-suppressor gene for destruction may be a key player in the development of lung cancer.
In the Nov. 17 issue of the Journal of the National Cancer Institute, scientists at the OSU Comprehensive Cancer Center (OSU CCC) note that the protein, called Pirh2, when overexpressed, diminishes the activity of the p53 gene – possibly the most powerful tumor suppressor in the entire genome. When it functions normally, p53 regulates several critical cellular processes, including cell growth and death, DNA repair, and angiogenesis, or the formation of new blood vessels. Studies show that p53 mutation is common, occurring in at least half of all cancer.
“The p53 gene is possibly the most important ‘manager’ in a cell. When it’s not working properly, it can be disastrous,” says Miguel Villalona, MD, senior author of the study. Villalona, a member of the OSU CCC's Experimental Therapeutics Program, says this is the first time Pirh2 has been implicated in the loss of p53 function in tumors.
Villalona and colleagues identified the link between Pirh2 and lung cancer development by evaluating Pirh2 expression in human and mouse lung tumor samples and comparing it with Pirh2 expression in normal tissue from the same samples. They found that Pirh2 expression was higher in 27 of 32 (84 percent) human lung cancers and in 14 of 15 (93 percent) mouse tumors than it was in the normal tissue.
“This is the first demonstration that Pirh2 expression is elevated in patients’ tumors, and it supports the notion that it may be an important molecule in the development of lung cancer,” says Gregory Otterson, MD, co-author of the study. Otterson is a member of the OSU CCC's Molecular Biology and Cancer Genetics Program.
Wenrui Duan, PhD, lead author of the study and a research scientist in the Department of Internal Medicine, says that when Pirh2 is overexpressed, it “acts like glue,” binding a substance called ubiquitin to p53 protein. Ubiquitin acts like a flag, telling the cell’s recycling center – the proteasome – that the proteins are ready to be destroyed. Destruction of the proteins essentially cripples p53 and opens the door to malignant transformation. Supporting that notion, the researchers discovered that p53 protein was more ubiquitinated in the mouse lung cancers than in the normal tissue, and that, generally, p53 expression was lower in tumor tissue than normal tissue.
Interestingly, additional analysis revealed that Pirh2 overexpression is not related to any mutations in p53 – only loss of function. “In effect, we’ve discovered that Prih2 is an oncogene. It promotes cancer by undermining the tumor suppressor’s ability to do its job,” says Duan. At the same time, these findings may offer scientists a new target for intervention. Villalona says new drugs are already on the market that inhibit the activity of the proteasome, and he suggests that these may be able to counter Pirh2’s oncogenic behavior by restoring p53 function. But other studies would be needed to show that.
Grants from the National Cancer Institute supported this study. Other OSU investigators who contributed to the project include: Li Gao, Lawrence Druhan, PhD; Wei-Guo Zhu, PhD; and Carl Morrison, MD, DVM.