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

Alla V. Ivanova; Sergey V. Ivanov; Ljudmila Prudkin; Daisuke Nonaka; Zhandong Liu; Anne Tsao; Ignacio Wistuba; Jack Roth; Harvey I. Pass

doi:10.1186/1476-4598-8-91

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

Alla V. Ivanova, Sergey V. Ivanov, Ljudmila Prudkin, Daisuke Nonaka, Zhandong Liu, Anne Tsao, Ignacio Wistuba, Jack Roth, Harvey I. Pass

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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.

Original language	English (US)
Article number	1476
Pages (from-to)	91
Number of pages	1
Journal	Molecular cancer
Volume	8
DOIs	https://doi.org/10.1186/1476-4598-8-91
State	Published - Oct 24 2009

ASJC Scopus subject areas

Molecular Medicine
Oncology
Cancer Research

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10.1186/1476-4598-8-91

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@article{c02acfc232d94c7fbd3113fce28e12d1,

title = "Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects",

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.",

author = "Ivanova, {Alla V.} and Ivanov, {Sergey V.} and Ljudmila Prudkin and Daisuke Nonaka and Zhandong Liu and Anne Tsao and Ignacio Wistuba and Jack Roth and Pass, {Harvey I.}",

note = "Funding Information: This project was supported in part by funds from the Early Detection Research Network NCI, NIH (5 U01 CA111295-02), the Mesothelioma Applied Research Foundation, Department of Veterans Affairs Merit Review Award, and by funds from Belluck and Fox, LLP New York, New York. We thank the NYU Cancer Institute Genomics Facility for expert assistance with gene expression profiling.",

year = "2009",

month = oct,

day = "24",

doi = "10.1186/1476-4598-8-91",

language = "English (US)",

volume = "8",

pages = "91",

journal = "Molecular cancer",

issn = "1476-4598",

publisher = "BioMed Central",

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TY - JOUR

T1 - Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects

AU - Ivanova, Alla V.

AU - Ivanov, Sergey V.

AU - Prudkin, Ljudmila

AU - Nonaka, Daisuke

AU - Liu, Zhandong

AU - Tsao, Anne

AU - Wistuba, Ignacio

AU - Roth, Jack

AU - Pass, Harvey I.

N1 - Funding Information: This project was supported in part by funds from the Early Detection Research Network NCI, NIH (5 U01 CA111295-02), the Mesothelioma Applied Research Foundation, Department of Veterans Affairs Merit Review Award, and by funds from Belluck and Fox, LLP New York, New York. We thank the NYU Cancer Institute Genomics Facility for expert assistance with gene expression profiling.

PY - 2009/10/24

Y1 - 2009/10/24

N2 - 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.

AB - 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.

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

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