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Melanoma Antigen A4 Is Expressed in Non–Small Cell Lung Cancers and Promotes Apoptosis

¹ Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; Departments of ² Anatomic Pathology and ³ Pulmonary, Allergy and Critical Care Medicine, The Cleveland Clinic Foundation; and ⁴ Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio

Requests for reprints: Tobias Peikert, Division of Pulmonary and Critical Care Medicine, Mayo Building, East 18, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-2495; Fax: 507-266-4372; E-mail: Peikert.Tobias{at}mayo.edu.

A variety of melanoma antigen A (MAGE-A) genes are commonly detected in non–small cell lung cancers. Their biological function is not well characterized but may involve the regulation of apoptosis and cell cycle progression. We hypothesized that MAGE-A4 is involved in the regulation of apoptosis. To investigate this, expression of MAGE-A was evaluated. MAGE-A4 was expressed in 48% of non–small cell lung carcinomas. Ninety percent of lung carcinomas expressing MAGE-A4 were classified as squamous cell carcinomas and 10% were adenocarcinomas. Tumor-free surrounding lung tissue was negative for MAGE-A4. A molecular clone of MAGE-A4 derived from human lung cancer was stably expressed in human embryonic kidney cells (293 cells) to evaluate effects on cell death. Overexpression of MAGE-A4 increased apoptosis as measured by the apoptotic index (P < 0.0001) and caspase-3 activity (P < 0.002). Exposure to 25 µmol/L etoposide, a chemotherapeutic agent, increased the apoptotic effect (P < 0.0001). Furthermore, we show that MAGE-A4 silencing using a small interfering RNA approach results in decreased caspase-3 activity in the squamous cell lung cancer cell line H1703 by 58% (P = 0.0027) and by 24% (P = 0.028) in 293/MAGE-A4 cells. These findings suggest that MAGE-A4 expression may promote tumor cell death, sensitize malignancies to apoptotic stimuli, such as chemotherapeutic agents, and therefore may represent a tumor suppressor protein. (Cancer Res 2006; 66(9): 4693-700)

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