Journal of the National Cancer Institute Advance Access published online on November 13, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm208
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Identification of the Retinoic Acid–Inducible Gprc5a As a New Lung Tumor Suppressor Gene
Affiliations of authors: Departments of Thoracic/Head and Neck Medical Oncology (QT, JF, TM, XY, JD, LL, LM, DL, RL), Clinical Cancer Prevention (JLC), Veterinary Medicine and Surgery (CSVP), and Biostatistics (JJL), The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Reuben Lotan, PhD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030 (e-mail: rlotan{at}mdanderson.org).
Background: Lung cancers develop via multiple genetic and epigenetic changes, including inactivation of tumor suppressor genes. We previously cloned human G protein–coupled receptor family C type 5A (GPRC5A), whose expression is suppressed in some human lung carcinoma cells, and its mouse homolog Gprc5a.
Methods: We generated Gprc5a knockout mice by homologous recombination and studied their phenotype by macroscopic observation and microscopic histologic analysis of embryos and lungs of 1- to 2-year-old mice. GPRC5A mRNA expression was analyzed by reverse transcription–polymerase chain reaction in surgical specimens of 18 human lung tumors and adjacent normal tissues and by analyzing previously published data from 186 lung tumor tissues of a variety of histologic types and 17 normal lung samples. Human embryonic kidney, human non–small-cell lung cancer, and mouse lung adenocarcinoma cells were transfected with a GPRC5A expression vector or a control vector, and colony formation in semisolid medium was assayed. Statistical tests were two-sided.
Results: Homozygous knockout mice developed many more lung tumors at 1–2 years of age (incidence: 76% adenomas and 17% adenocarcinomas) than heterozygous (11% adenomas) or wild-type (10% adenomas) mice. Human GPRC5A mRNA levels were lower in most (11 of 18 [61%]) human lung tumors than in adjacent normal tissues. The mean GPRC5A mRNA level in adenocarcinoma (n = 139), squamous cell carcinoma (n = 21), small-cell lung cancer (n = 6), and carcinoid (n = 20) tissues was 46.2% (P = .014), 7.5% (P<.001), 5.3% (P<.001), and 1.8% (P<.001), respectively, that in normal lung tissues (n = 17) GPRC5A transfection suppressed colony formation in semisolid medium of immortalized human embryonic kidney, human non–small-cell lung cancer, and mouse lung adenocarcinoma cells by 91%, 91%, and 68%, respectively, compared with vector controls (all P<.001).
Conclusions: Gprc5a functions as a tumor suppressor in mouse lung, and human GPRC5A may share this property. The Gprc5a-deficient mouse is a novel model to study lung carcinogenesis and chemoprevention.
| CONTEXT AND CAVEATS Prior knowledge Multiple genetic and epigenetic changes contribute to the development of lung cancer. The expression of G protein–coupled receptor family C type 5A (GPRC5A) is suppressed in some human lung cancers. Study design A novel Gprc5a knockout mouse model, comparison of GPRC5A expression in human lung cancer and normal lung tissue, and in vitro colony formation assays of human and mouse tumor cell lines expressing exogenous human GPRC5A. Contributions Homozygous Gprc5a knockout mice developed more lung tumors during 1–2 years than heterozygous or wild-type mice. GPRC5A expression was lower in most of the lung tumors than in normal lung tissues. Exogenous GPRC5A expression reduced colony formation in tumor cell lines. Implications Gprc5a functions as a lung tumor suppressor in the mouse. The human GPRC5A may also function as a tumor suppressor in human lung cancer. Limitations Other genetic or epigenetic changes may have occurred in the mouse model. Mice were not exposed to carcinogens or proinflammatory agents, which are important in the development of human lung cancer.
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Manuscript received February 12, 2007; revised September 5, 2007; accepted October 2, 2007.
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J Natl Cancer Inst 2007 99: 1654-1655.
J Natl Cancer Inst 2007 99: 1653.
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