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Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, California 94115

Malignant pleural mesothelioma is a rare and aggressive tumor characterized by rapid progression, late metastases, and poor prognosis. In this study, we investigated the expression of survivin, a member of the inhibitors of apoptosis protein gene family, in mesothelioma and an antisense oligonucleotide-based gene therapy for mesothelioma using survivin as a target. Initially, we documented the expression of survivin in human mesothelioma cell lines and fresh tissues using reverse transcription-PCR and Western blot analysis. Our results showed that survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed. To investigate the use of survivin as a therapeutic target on mesothelioma, we carried out transfections with antisurvivin oligonucleotides to induce apoptosis in mesothelioma cell lines MS-1 and H28. Results from cellular transfection and subsequent analysis using the flow cytometry demonstrated that antisurvivin oligonucleotides induced significantly greater apoptosis rates in the survivin-positive mesothelioma cell line H28 (42.5%) as compared with the control oligonucleotides (16.2%; P < 0.001). The survivin-negative cell line LRK1A (survivin-/-) did not apoptose with antisense oligonucleotides. Furthermore, time course evaluation by Western blot analysis showed that survivin was inhibited by antisurvivin oligonucleotides within 12 h after transfection. Our results show, for the first time, that survivin, an inhibitors of apoptosis protein family gene member, is highly overexpressed in malignant pleural mesothelioma. Down-regulation of survivin by a targeted antisense oligonucleotide appears to be an effective gene therapy approach to the treatment of mesothelioma.

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