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The Antiapoptotic Protein BAG3 Is Expressed in Thyroid Carcinomas and Modulates Apoptosis Mediated by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Functional Genomic Unit (G.C., M.M., E.V., R.P., C.A., L.P.), National Cancer Institute, Fondazione G. Pascale, 80131 Naples, Italy; Department of Surgical and Oncological Sciences (M.Z., M.T., G.S.), University of Palermo, 90100 Palermo, Italy; and Department of Pharmaceutical Sciences (M.A., A.B., A.R., M.F., A.G., A.T., M.P., L.M., M.A.B., M.C.T., A.L.), University of Salerno, 84084 Fisciano, Italy

Address all correspondence and requests for reprints to: Maria Caterina Turco, M.D., Ph.D., Dipartimento di Scienze Farmaceutiche (DiFarma), University of Salerno, Via ponte don Melillo, 84084 Fisciano, Italy. E-mail: mcturco{at}unisa.it.

Context: We previously showed that BAG3 protein, a member of the BAG (Bcl-2-associated athanogene) co-chaperone family, modulates apoptosis in human leukemias. The expression of BAG3 in other tumor types has not been extensively investigated so far.

Objective: The objective of this study was to analyze BAG3 expression in thyroid neoplastic cells and investigate its influence in cell apoptotic response to TNF-related apoptosis-inducing ligand (TRAIL).

Design, Setting, and Patients: We investigated BAG3 expression in human thyroid carcinoma cell lines, including NPA, and the effect of BAG3-specific small interfering RNA on TRAIL-induced apoptosis in NPA cells. Subsequently, we analyzed BAG3 expression in 30 benign lesions and 56 carcinomas from patients of the Naples Tumor Institute Fondazione Senatore Pascale.

Main Outcome Measures: The main outcome measures were: analysis of BAG3 protein in NPA cells by Western blot and immunocytochemistry; analysis of apoptosis in TRAIL-stimulated NPA cells by flow cytometry; and evaluation of BAG3 expression in specimens from thyroid lesions by immunohistochemistry.

Results: BAG3 was expressed in human thyroid carcinoma cell lines; small interfering RNA-mediated downmodulation of its levels significantly (P < 0.0195) enhanced NPA cell apoptotic response to TRAIL. The protein was not detectable in 19 of 20 specimens of normal thyroid or goiters, whereas 54 of 56 analyzed carcinomas (15 follicular, 28 papillary, and 13 anaplastic) were clearly positive for BAG3 expression.

Conclusions: BAG3 downmodulates the apoptotic response to TRAIL in human neoplastic thyroid cells. The protein is specifically expressed in thyroid carcinomas and not in normal thyroid tissue or goiter.