Expression patterns of inhibitor of apoptosis proteins in malignant pleural mesothelioma

The Journal of Pathology. 2007 Mar;211(4):447-54. [Link]

GJ Gordon ^{1 *}, M Mani ¹, L Mukhopadhyay ¹, L Dong ¹, HR Edenfield ¹, JN Glickman ², BY Yeap ³, DJ Sugarbaker ¹, R Bueno ¹

¹The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA

²Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA

³Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA

email: GJ Gordon (ggordon@partners.org)

Abstract

Inhibitor of apoptosis proteins (IAPs) comprise a family of structurally similar proteins, five of which are widely studied in the context of cancer: IAP-1/MIHC/cIAP2, IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP. IAPs are overexpressed by most neoplasms, promote tumour cell survival after a wide variety of apoptotic stimuli, and frequently have gene and/or protein expression patterns associated with a relatively poor prognosis. However, many IAPs are also expressed by normal tissues, can facilitate apoptotic cell death, and have expression patterns associated with a relatively favourable prognosis in some cases. The result is that the precise role(s) of IAPs in human tumours is not exactly known. It has been previously reported that IAP-1 is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Given the high homology of IAP family members, it is likely that other IAPs will be important in MPM. In the present study, the gene and protein expression patterns of IAP-1, IAP-2, survivin, livin, and XIAP have been determined in MPM cell lines (n = 9) and a large number of MPM tumours using high-density oligonucleotide microarrays (n = 40) and an MPM tissue array (n = 66). Human tumours were linked to clinical data and it was found that IAP-1 and survivin mRNA expression patterns were associated with a relatively shorter patient survival, while those of XIAP and livin were associated with a relatively longer patient survival. Abundant protein for all IAPs was also detected in MPM tumours, where they were expressed primarily in the cytoplasm. Only IAP-1 and livin protein was expressed in the nucleus of MPM tumours. These results provide the rationale for additional study of this gene family in MPM and cancer in general.