Research

Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects

Alla V Ivanova¹ , Sergey V Ivanov² , Ljudmila Prudkin³ , Daisuke Nonaka² , Zhandong Liu⁴ , Anne Tsao³ , Ignacio Wistuba³ , Jack Roth⁵ and Harvey I Pass²

¹  Hematology/Oncology Division, Vanderbilt Medical Center, Nashville, TN, USA

²  Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY, USA

³  Department of Thoracic/Head and Neck Medical Oncology, University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX, USA

⁴  Genomics and Computational Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

⁵  Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

author email corresponding author email

Molecular Cancer 2009, 8:91doi:10.1186/1476-4598-8-91

Published:	24 October 2009

Abstract

Background

FUS1/TUSC2 is a novel tumor suppressor located in the critical 3p21.3 chromosomal region frequently deleted in multiple cancers. We previously showed that Tusc2-deficient mice display a complex immuno-inflammatory phenotype with a predisposition to cancer. The goal of this study was to analyze possible involvement of TUSC2 in malignant pleural mesothelioma (MPM) - an aggressive inflammatory cancer associated with exposure to asbestos.

Methods

TUSC2 insufficiency in clinical specimens of MPM was assessed via RT-PCR (mRNA level), Representational Oligonucleotide Microarray Analysis (DNA level), and immunohistochemical evaluation (protein level). A possible link between TUSC2 expression and exposure to asbestos was studied using asbestos-treated mesothelial cells and ROS (reactive oxygen species) scavengers. Transcripional effects of TUSC2 in MPM were assessed through expression array analysis of TUSC2-transfected MPM cells.

Results

Expression of TUSC2 was downregulated in ~84% of MM specimens while loss of TUSC2-containing 3p21.3 region observed in ~36% of MPMs including stage 1 tumors. Exposure to asbestos led to a transcriptional suppression of TUSC2, which we found to be ROS-dependent. Expression array studies showed that TUSC2 activates transcription of multiple genes with tumor suppressor properties and down-regulates pro-tumorigenic genes, thus supporting its role as a tumor suppressor. In agreement with our knockout model, TUSC2 up-regulated IL-15 and also modulated more than 40 other genes (~20% of total TUSC2-affected genes) associated with immune system. Among these genes, we identified CD24 and CD274, key immunoreceptors that regulate immunogenic T and B cells and play important roles in systemic autoimmune diseases. Finally, clinical significance of TUSC2 transcriptional effects was validated on the expression array data produced previously on clinical specimens of MPM. In this analysis, 42 TUSC2 targets proved to be concordantly modulated in MM serving as disease discriminators.

Conclusion

Our data support immuno-therapeutic potential of TUSC2, define its targets, and underscore its importance as a transcriptional stimulator of anti-tumorigenic pathways.