The authors found that, mice with both of their GPRC5A genes suppressed developed 76 percent precancerous lesions called adenomas in their lungs and another 17 percent developed malignancies called adenocarcinomas normally until their second year of life. Only 10 percent of mice with both GPRC5A genes intact developed adenomas, and only 11 percent with one working version of the gene while none of the mice in the latter two groups developed lung cancer.
The experiment involved the expression of the gene compared in 18 pairs of human non-small lung cancer and adjacent normal tissues. In 11 cases or 61 percent, the tumours had lower levels of GPRC5A messenger RNA than the nearby normal tissue. Two had higher levels of expression in the tumour and one pair had similar levels in both tissues, while four had no expression in either sample.
The researchers then compared 186 lung tumours to 17 normal control tissues using gene expression profiling with a microarray. The four tumour types all had a fraction of the GPRC5A gene expression shown in the normal cells: adenocarcinoma 46.2 percent; squamous cell carcinoma at 7.5 percent; small-cell lung cancer at 5.3 percent; and carcinoid at 1.8 percent.
In the end they inserted the GPRC5A gene back into lung cancer cell lines in a laboratory experiment and suppressed colony formation of human lung cancer cells by 91 percent in two cell lines. "In humans, lung adenocarcinomas are the most common type of lung cancer and the major cause of death from this disease," said senior author Reuben Lotan, Ph.D., professor in M. D. Anderson's Department of Thoracic/ Head and Neck Medical Oncology.
"Further study substantiating the role of the GPRC5A gene in human lung cancer could lead to the development of novel approaches for lung cancer prevention, diagnosis and treatment," he said. The researchers who had previously shown that Gprc5a protein was detected in the lungs more than in any other tissue and was underexpressed in human non-small cell lung cancer were now in head and neck with squamous cell carcinoma.
The experiments were conducted to follow up these earlier clues of a tumor-suppressing role for the genes. It stated that loss of a tumor-suppressor gene product such as Gprc5a protein is an important step in cancer development. The team also discovered that the tumors generated in the mice without the genes lacked mutations to the K-Ras gene- a common oncogene that fuels cancer growth.
"This may be important because the carcinogenesis pathway observed in our model may be relevant to the more than 65 percent of human non-small cell lung cancers that don't have K-Ras mutations," said Reuben Lotan. "These findings suggest that GPRC5A can suppress lung cancer development in humans as well as mice," he added.
The study appears in the Nov. 21 edition of The Journal of the National Cancer Institute.